WO2005061450A2 - Hiv protease inhibiting sulfonamides - Google Patents

Hiv protease inhibiting sulfonamides Download PDF

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Publication number
WO2005061450A2
WO2005061450A2 PCT/US2004/037745 US2004037745W WO2005061450A2 WO 2005061450 A2 WO2005061450 A2 WO 2005061450A2 US 2004037745 W US2004037745 W US 2004037745W WO 2005061450 A2 WO2005061450 A2 WO 2005061450A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
methyl
amino
benzyl
sulfonyl
Prior art date
Application number
PCT/US2004/037745
Other languages
French (fr)
Other versions
WO2005061450A3 (en
Inventor
Charles A. Flentge
Hui-Ju Chen
David A. Degoey
William J. Flosi
David J. Grampovnik
Peggy P. Huang
Dale J. Kempf
Larry L. Klein
Allan C. Krueger
Darold L. Madigan
John T. Randolph
Minghua Sun
Ming C. Yeung
Chen Zhao
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to MXPA06006610A priority Critical patent/MXPA06006610A/en
Priority to AT04810802T priority patent/ATE452889T1/en
Priority to EP04810802A priority patent/EP1709037B8/en
Priority to CA002549389A priority patent/CA2549389A1/en
Priority to DE602004024830T priority patent/DE602004024830D1/en
Priority to JP2006543826A priority patent/JP2007513944A/en
Publication of WO2005061450A2 publication Critical patent/WO2005061450A2/en
Publication of WO2005061450A3 publication Critical patent/WO2005061450A3/en
Priority to HK07103390.3A priority patent/HK1100037A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/65—Tetracyclines
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/32—One oxygen atom
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
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    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Definitions

  • the present invention relates to novel compounds and a composition and a method for inhibiting human immunodeficiency virus (HIN) protease, a composition and method for inhibiting or treating an HIN infection, processes for making the compounds and synthetic intermediates employed in the processes.
  • HIN human immunodeficiency virus
  • HIN protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products.
  • HIN protease processes the gag precursor into core proteins and also processes the pol precursor into reverse transcriptase and protease.
  • the correct processing of the precursor polyproteins by HIN protease is necessary for the assembly of infectious virions. Therefore, inhibition of HIN protease provides a useful target for development of therapeutic agents for treatment of HIN infection.
  • inhibitors of HIN protease have become an important class of therapeutic agents for inhibition and treatment of HIN infection in humans.
  • HIN protease inhibitors are especially effective when administered in combination with other classes of HIN therapeutic agents, especially inhibitors of HIN reverse transcriptase, in "cocktails" of HIV therapeutic agents.
  • the HIN protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir/ritonavir, fosamprenavir, and atazanavir have been approved in the U.S. for treatment of HIN infection.
  • HIV protease inhibitors that are very potent, that have reduced side-effects and that are effective against resistant strains of HIV.
  • X is O, S orNH;
  • Y is O, S orNH;
  • R 8a and R 8b are, at each occurrence, independently selected from the group consisting of alkyl, arylalkyl and heteroarylalkyl; wherein each R 8a and R 8b is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of alkyl, nitro, hydroxy, alkoxy, amino, formyl, halo, haloalkyl, hydroxyalkyl, alkoxyalky aminoalkyl and formylalkyl;
  • R 13a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R 13a
  • the present invention also provides the processes of making a compound of the present invention and intermediates employed in the processes.
  • the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, and a pharmaceutically acceptable carrier.
  • the present invention yet further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, and one, two, three, four, five or six agents selected from the group consisting of a second HIV protease inhibitor, a HIV reverse transcriptase inhibitor, an HIV entry/fusion inhibitor, an HIV integrase inhibitor and an HIV budding/maturation inhibitor, and a pharmaceutically acceptable carrier.
  • the present invention still further provides a method of inhibiting the replication of an HIV protease inhibitor, a HIV reverse transcriptase inhibitor, an HIV entry/fusion inhibitor, an HIV integrase inhibitor and an HIV budding/maturation inhibitor, and a pharmaceutically acceptable carrier.
  • the present invention still further provides a method of inhibiting the replication of an HIV protease inhibitor, a HIV reverse transcriptase inhibitor,
  • HIV virus comprising contacting said virus with a therapeuctially effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof.
  • the present invention still further provides a method of inhibiting the replication of an
  • the present invention still further provides a method of inhibiting an HIV protease comprising contacting said HIV protease with a therapeuctially effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof.
  • the present invention still further provides a method of inhibiting an HIV protease comprising contacting said HIV protease with any one of the pharmaceutical composition of the present invention.
  • the present invention also provides a method of treating or preventing an HIV infection comprising administering to a patient in need of such treatment a therapeuctially effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof.
  • the present invention also provides a method of treating or preventing an HIV infection comprising administering to a patient in need of such treatment any one of the phannaceutical composition of the present invention.
  • activated carboxylic acid group refers to acid halides such as acid chlorides and also refers to activated ester derivatives including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, anhydrides derived from reaction of the carboxylic acid with N,N'-carbonyldiimidazole and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N- hydroxy-5-norbornene-2,3-dicarboximide derived esters, 2,4,5-trichlorophenol derived esters, p-nitro
  • alkanoyl refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.
  • alkanoyl include methylcarbonyl, ethylcarbonyl, tert-butylcarbonyl and the like.
  • alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon containing 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Examples of alkyl groups include butyl, methyl, 1-methylpropyl, 2-methylbutyl, tert-butyl, isopropyl, and the like.
  • alkylamino refers to -N(H)R 90 wherein R 90 is alkyl.
  • alkylaminocarbonyl refers to an alkylamino group attached to the parent molecular moiety through a carbonyl group.
  • alkenyl refers to a straight or branched chain group of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms containing at least one carbon-carbon double bond. Examples of alkenyl groups include allyl, propenyl, 3-methyl-2-butenyl, and the like.
  • alkynyl refers to a straight or branched chain hydrocarbon of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms containing at least one carbon-carbon triple bond.
  • alkynyl groups include ethynyl, 2-methyl-3-butynyl, 3-pentynyl, and the like.
  • alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen atom. Examples of alkoxy groups include tert-butoxy, methoxy, isopropoxy, and the like.
  • alkoxyalkyl refers to an alkyl group substituted by at least one alkoxy group.
  • alkoxycarbonyl refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl groups include tert-butoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, and the like.
  • amino refers to -NH 2 .
  • aminoalkyl refers to an amino group appended to the parent molecular moiety through an alkyl group as defined herein.
  • aryl refers to a phenyl group, or a bicyclic or tricyclic hydrocarbon fused ring systems wherein one or more of the rings is a phenyl group.
  • Bicyclic fused ring systems have a phenyl group fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group.
  • Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group.
  • aryl groups include anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.
  • the aryl groups of the present invention can be connected to the parent molecular moiety through any substitutable carbon atom of the group.
  • the aryl groups of the present invention can be substituted or unsubstituted.
  • arylalkyl refers to an aryl group attached to the parent molecular moiety through an alkyl group.
  • cyano refers to -CN.
  • cyanoalkyl refers to a cyano group attached to the parent molecular moiety through an alkyl group.
  • cycloalkenyl refers to a non-aromatic, partially unsaturated, monocyclic, bicyclic or tricyclic ring system, having three to fourteen carbon atoms and zero heteroatom.
  • cycloalkenyl groups examples include cyclohexenyl, octahydronaphthalenyl, norbornylenyl, and the like.
  • the cycloalkenyl groups of the present invention can be unsubstituted or substituted.
  • cycloalkenylalkyl refers to a cycloalkenyl group attached to the parent molecular moiety through an alkyl group.
  • cycloalkyl refers to a saturated monocyclic, bicyclic.; or tricyclic hydrocarbon ring system having three to fourteen carbon atoms and zero heteroatom.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[3.1.1]heptyl, 6,6-dimethylbcyclo[3.1.1]heptyl, adamantyl, and the like.
  • the cycloalkyl groups of the present invention can be unsubstituted or substituted.
  • dialkylamino refers to -NR 90 R 91 , wherein R 90 and R 91 are alkyls.
  • dialkylaminocarbonyl refers to a dialkylamino group as defined herein, appended to the parent molecular moiety through a carbonyl group.
  • formyl refers to a -C(O)H group.
  • formylalkyl refers to a formyl group appended to the parent molecular moiety through an alkyl group.
  • haloalkenyl refers to an alkenyl group substituted by one, two, three, or four halogen atoms.
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkoxyalkyl refers to a haloalkoxy group attached to the parent molecular moiety through an alkyl group, as defined herein.
  • haloalkyl refers to an alkyl group substituted by one, two, three, or four halogen atoms.
  • haloalkynyl refers to an alkynyl group substituted by one, two, three, or four halogen atoms.
  • heteroaryl refers to an aromatic five- or six-membered ring where at least one atom is selected from the group consisting of N, O, and S, and the remaining atoms are carbon.
  • heteroaryl also includes bicyclic systems where a heteroaryl ring is fused to a phenyl group, a monocyclic cycloalkyl group, as defined herein, a heterocycle group, as defined herein, or an additional heteroaryl group.
  • heteroaryl also includes tricyclic systems where a bicyclic system is fused to a phenyl group, a monocyclic cycloalkyl group, as defined herein, a heterocycle group, as defined herein, or an additional heteroaryl group.
  • the heteroaryl groups are connected to the parent molecular moiety through any substitutable carbon or nitrogen atom in the groups.
  • heteroaryl groups include benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, benzofuranyl, dihydrobenzothiazolyl, furanyl (furyl), imidazolyl, 3H-[4,5-b]pyridinyl, indazolyl, indolyl, isoindolyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, oxazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, tetrazolyl, pyridoimidazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, tetrahydroquinolinyl, triazinyl,
  • heteroaryl groups of the present invention can be substituted or unsubstituted.
  • the nitrogen heteroatoms can be optionally quatemized or oxidized to the N-oxide.
  • the nitrogen containing rings can be optionally N-protected.
  • heteroarylalkyl refers to refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group.
  • heterocycle refers to cyclic, non-aromatic, saturated or partially unsaturated, three, four, five-, six-, or seven-membered rings containing at least one atom selected from the group consisting of oxygen, nitrogen, and sulfur.
  • heterocycle also mcludes bicyclic systems where a heterocycle ring is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or an additional monocyclic heterocycle group.
  • heterocycle also includes tricyclic systems where a bicyclic system is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or an additional monocyclic heterocycle group.
  • heterocycle groups of the invention are connected to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group.
  • heterocycle groups include benzoxazinyl, 1,3- benzodioxol, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, tetrahydrofuranyl, hexahydrofurofuranyl, hexahydrofuropyranyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomoipholinyl, tetrahydropyranyl, and the like.
  • heterocycle groups of the present invention can be substituted or substituted.
  • the nitrogen heteroatoms can be optionally quatemized or oxidized to the N-oxide.
  • the nitrogen containing heterocyclic rings can be optionally N-protected.
  • heterocyclealkyl refers to refers to a heterocycle group attached to the parent molecular moiety through an alkyl group.
  • hydroxy or “hydroxyl” as used herein, refers to -OH.
  • hydroxyalkyl refers to an alkyl group as substituted by at least one hydroxy group.
  • nitro refers to -NO .
  • nitroalkyl refers to an alkyl group substituted by at least one nitro group.
  • thioalkoxy refers to an alkyl group as defined herein, appended to the parent molecular moiety through a sulfur atom.
  • thioalkoxyalkyl refers to an thioalkoxy group as defined herein, appended to the parent molecular moiety through a alkyl group.
  • alkanoyl alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkynyl, aminoalkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, dialkylamino, dialkylaminocarbonyl, formylalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkynyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, nitroalkyl, thioalkoxy and thioalkoxyalkyl may be unsubstituted or substituted.
  • the present invention provides
  • R 5 is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -OalkylSO 2 alkyl, -O-heterocycle, -alkyl-O-aryl or -O-alkyl-heteroaryl; wherein the heterocycle, aryl or heteroaryl moiety of -O-heterocycle, -alkyl-O-aryl and -O-alkyl-heteroaryl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -SH, -S(alkyl), -SO 2 (alkyl), -N(H)C
  • R 12 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or cycloalkenylalkyl; wherein each R 12 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, alkoxy cyano, nitro and halo;
  • R a and R b together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -SH, -S(
  • the present invention provides a compound of formula (I) wherein Ri is OH and R 2 is H.
  • the present invention provides a compound of formula (I) wherein R ⁇ is OH, R 2 is H, X is O and Y is O.
  • the present invention provides a compound of formula (I) wherein wherein R ⁇ is OH, R is H, X is O, Y is O, and R 3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSR a , -alkylSORa, -alkylSO 2 R a or -alkylNRaRb.
  • the present invention provides a compound of formula (I) wherein R ⁇ is OH, R 2 is H, X is O, Y is O, R 3 is alkyl or cycloalkylalkyl and R 4 is aryl or heteroaryl.
  • R 1 is OH, R 2 is H, X is O, Y is O, R 3 is alkyl or cycloalkylalkyl and i is phenyl.
  • the present invention provides a compound of formula (I) wherein R 1 is OH, R 2 is H, X is O, Y is O, R 3 is alkyl or cycloalkylalkyl and R t is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -O ia, -NR a 4b and
  • -C(R 4b ) NOR 4a ; wherein R ⁇ and R ⁇ are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (I) wherein Ri is OH, R 2 is H, R 3 is alkyl or cycloalkylalkyl, R4 is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR 4a , -NR ⁇ R ⁇ and -C ⁇ NOR ⁇ , R is phenylmethyl and R 7 is alkyl; wherein R ⁇ and n, are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (I) wherein Ri is OH, R 2 is H, R 3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentyhnethyl, R 4 is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORia, R is phenylmethyl and R 7 is alkyl; wherein R a and R are independently selected from the group consisting of hydrogen and alkyl.
  • Exemplary compounds of the present invention having formula (I) include, but not limited to, the following: hexahydrofuro[2,3-b]furan-3-yl (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- '
  • R a and R together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -SH, -S(alkyl
  • the present invention provides a compound of formula (II) wherein Ri is OH and R 2 is H.
  • the present invention provides a compound of formula (II) wherein Ri is OH, R 2 is H and R 3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSR a , -alkylSOR a , -alkylSO 2 R a or -alkylNR a R b .
  • the present invention provides a compound of formula (II) wherein Ri is OH, R 2 is H, R 3 is alkyl or cycloalkyl and is aryl or heteroaryl.
  • the present invention provides a compound of formula (II) wherein Ri is
  • Exemplary compounds of the present invention of formula (II) include, but not limited to, the following: tert-butyl (lS)-l-[( ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)-
  • the present invention provides a compound of formula (III)
  • R la is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each R la is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -OR a , -SR a , -SOR a ,
  • R 2 is H;
  • the present invention provides a compound of formula (III) wherein Ri is OH and R 2 is H.
  • the present invention provides a compound of formula (III) wherein Ri is OH, R 2 is H, X is O and R 3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSR a , -alkylSOR a , -alkylSO 2 R a or -alkylNR a R b .
  • the present invention provides a compound of formula (III) wherein Ri is OH, R 2 is H, X is O, R 3 is alkyl or cycloalkyl and j is aryl or heteroaryl.
  • the present invention provides a compound of formula (III) wherein Ri is OH, R 2 is H, X is O, R 3 is alkyl or cycloalkylalkyl and R 4 is phenyl.
  • the present invention provides a compound of formula (III) wherein Ri is OH, R 2 is H, X is O, R 3 is alkyl or cycloalkylalkyl and R is, phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -O 4 a , -NR ⁇ ⁇ and
  • R a and n are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (III) wherein Ri is OH, R 2 is H, X is O, R 3 is alkyl or cycloalkylalkyl, R is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR 4a , -NR a R 4b and
  • R 7 is alkyl; wherein ⁇ a and R are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (III) wherein R ⁇ is OH, R 2 is H, X is O, R 3 is alkyl or cycloalkylalkyl, is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR ta , -NR ⁇ R ⁇ , and
  • R 7 is alkyl and R is phenylmethyl; wherein R ⁇ and R 4b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (III) wherein Ri is OH, R 2 is H, X is O, R 3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, R is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR 4a , -NR a R 4b and -CQ HJ ⁇ NOR ⁇ , and R 7 is CI alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl and R is phenylmethyl; wherein i a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • Exemplary compounds of the present invention of formula (III) include, but not limited to, the following: (2S)-N- ⁇ (1 S,2R)-1 -benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2-(3 - ⁇ [2-(methoxymethyl)- 1 ,3 -thiazol-4-yl]methyl ⁇ -2-oxoimidazolidin- 1 -yl)-3 -methylbutanamide; (2S)-N- ⁇ (1S,2R)-1 -benzyl-2-hydroxy-3-[( ⁇ 4-[(E)-
  • the present invention provides a compound of formula (IV) wherein Ri is OH and R 2 is H.
  • the present invention provides a compound of formula (IV) wherein Ri is OH, R 2 is H, X is O and R 3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSR a , -alkylSOR a , -alkylSO 2 R a or -alkylNR a R .
  • the present invention provides a compound of formula (IV) wherein R ⁇ is OH, R 2 is H, X is O, R 3 is alkyl or cycloalkyl and i is aryl or heteroaryl.
  • the present invention provides a compound of formula (IV) wherein Ri is OH, R 2 is H, X is O, R 3 is alkyl or cycloalkyl and R 4 is phenyl.
  • Exemplary compounds of the present invention of formula (IV) include, but not limited to, the following: (2S)-N- ⁇ (1 S,2R)-1 -benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenylJsulfonyl)(isobutyl)amino]propyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxo-2,3-dihydro-lH-imidazol-l-ylJbutanamide; and (2S,3 S)-N- ⁇ (1 S,2R)- 1 -benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propylJ-2-[3-( ⁇ 2-[N- hydroxy ethanimidoylJpyridin-4-
  • X is O, S orNH
  • Y is O, S or NH
  • the present invention provides a compound of formula (V) wherein Ri is OH and R 2 is H.
  • the present invention provides a compound of formula (V) wherein Ri is OH, R 2 is H, X is O, Y is O and R 3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSR a , -alkylSOR a , -alkylSO 2 R a or -alkylNR a R .
  • the present invention provides a compound of formula (V) wherein R ⁇ is OH, R 2 is H, X is O, Y is O, R 3 is alkyl or cycloalkyl and Rt is aryl or heteroaryl.
  • the present invention provides a compound of fo ⁇ nula (V) wherein Ri is OH, R 2 is H, X is O, Y is O, R 3 is alkyl or cycloalkyl and t is phenyl.
  • the present invention provides a compound of formula (V) wherein Ri is
  • R 2 is H
  • X is O
  • Y is O
  • the present invention provides a compound of formula (V) wherein Ri is
  • R 2 is H
  • X is O
  • Y is O
  • R 3 is alkyl or cycloalkylalkyl
  • R 7 is alkyl
  • Ri a and t b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (V) wherein Ri is
  • R 2 is H
  • X is O
  • Y is O
  • R 3 is alkyl or cycloalkylalkyl
  • R is alkyl and R is phenylmethyl
  • ta and Ri b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (V) wherein Ri is
  • R 2 is H
  • X is O
  • Y is O
  • R 3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl
  • R 7 is alkyl and R is phenylmethyl; wherein R 4a and tb are independently selected from the group consisting of hydrogen and alkyl.
  • Exemplary compounds of the present invention of formula (V) include, but not limited to, the following: (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyljphenylj sulfonyl)(isobutyl)amino]propyl ⁇ -2-(3 - ⁇ [2-(methoxymethyl)- l,3-thiazol-4-yl]methyl ⁇ -2,4-dioxo-l-imidazolidinyl)-3-methylbutanamide; (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl] ⁇ henyl ⁇ sulfonyl)(isobutyl)amino]propylJ-3-methyl-2-[3-(3- nitrobenzyl)-2,4-dioxo- 1 -imid
  • the present invention provides a compound of formula (NI) (NI) or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrag, or combination thereof, wherein X is O, S or ⁇ H;
  • Ri 3a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein
  • R a and R b together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -SH, -S(
  • the present invention provides a compound of formula (VI) wherein R ⁇ is OH and R 2 is H.
  • the present invention provides a compound of formula (VI) wherein ⁇ is OH, R 2 is H, X is O and R 3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSR a , -alkylSOR a , -alkylSO 2 R a or -alkylNR a R .
  • the present invention provides a compound of formula (VI) wherein Ri is OH, R 2 is H, X is O, R 3 is alkyl or cycloalkyl and R t is aryl or heteroaryl.
  • the present invention provides a compound of formula (VI) wherein Ri is OH, R 2 is H, X is O, R 3 is alkyl or cycloalkylalkyl and R 4 is phenyl.
  • Exemplary compounds of the present invention of fonnula (VI) include, but not limited to, the following: (2S,3S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-methyl-2-( ⁇ [methyl(2- pyridinylmethyl)amino]carbonyl ⁇ amino)pentanamide; (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2-( ⁇ [[(2-isopropyl- 1,3- thiazol-4-yl)methyl](methyl)amino]carbonyl ⁇ amino)-3-methylbut
  • A is R 5 C(O , R 6 SO 2 -,
  • X is O, S or ⁇ H
  • Y is O, S or ⁇ H
  • R la is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each R la is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -OR a , -SR a , -SOR a ,
  • R 2 is H;
  • R 3 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cycloalkenylalkyl, cyclo
  • R 8a and R 8b are, at each occurrence, independently selected from the group consisting of allcyl, arylalkyl and heteroarylalkyl; wherein each R 8a and R 8b is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of alkyl, nitro, hydroxy, alkoxy, amino, formyl, halo, haloalkyl, hydroxyalkyl, alkoxyalky aminoalkyl and formylalkyl;
  • Ri 2 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or cycloalkenylalkyl; wherein each Ri 2 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, alkoxy cyano, nitro and halo;
  • the present invention provides a compound of formula (VII) wherein R ⁇ is OH and R 2 is H.
  • the present invention provides a compound of formula (Nil) wherein Ri is OH, R 2 is H, X is O and Y is O.
  • the present invention provides a compound of formula (Nil) wherein wherein Ri is OH, 2 is H, X is O, Y is O and R 3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSR a , -alkylSOR a , -alkylSO 2 R a or -alkyl ⁇ R a R .
  • the present invention provides a compound of formula (Nil) wherein Ri is OH, R 2 is H, X is O, Y is O, R 3 is alkyl or cycloalkylalkyl and R 4 is aryl or heteroaryl.
  • the present invention provides a compound of formula (Nil) wherein Ri is OH, R 2 is H, X is O, Y is O, R 3 is alkyl or cycloalkylalkyl and t is phenyl.
  • the present invention provides a compound of formula (Nil) wherein Ri is OH, R 2 is H, X is O, Y is O, R 3 is alkyl or cycloalkylalkyl and 4 is phenyl substituted with
  • R ta and t are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (Nil) wherein Ri is OH, R 2 is H, X is O, Y is O, R 3 is alkyl or cycloalkylalkyl, R 4 is phenyl substituted with 0,
  • the present invention provides a compound of fo ⁇ nula (VII) wherein Ri is OH, R 2 is H, R 3 is C3, alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, t is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, R is phenylmethyl and R 7 is CI alkyl, C2 alkyl, C3 allcyl, C4 alkyl or C5 alkyl; wherein Rt a and R 4 are independently selected from the group consisting of hydrogen and alkyl.
  • VII fo ⁇ nula
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound, or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrag, or combination thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, one, two, three, five or six second HIV protease inhibitors, and a pha ⁇ naceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of ane ester, prodrug, salt of a prodrug, or combination thereof, one, two, three, four, five or six second HIV protease inhibitors selected from the group consisting of ritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir, nelfmavir, tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L- 756423, RO0334649, KNI-272, DPC-681, DPC-684 and GW640385X, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, one, two, three, four, five or six HIV reverse transcriptase inhibitors, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound, or combination of compounds of formula (I), (II), (III), (IN), (N), (NI) or (Nil), or a pha ⁇ naceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, one, two, three, four, five or six HIV reverse transcriptase inhibitors selected from the group consisting of lamivudine, stavudine, zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIV-210, Racivir ( ⁇ -FTC), D-D4FC (Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz, capravirine, e
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, one, two, three, four, five or six HIV entry/fusion inhibitors, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pha ⁇ naceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, one, two, three, four, five or six HIV entry/fusion inhibitors selected from the group consisting of enfuvirtide (T-20), T-1249, PRO 2000, PRO 542, PRO 140, AMD-3100, BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D (SCH-D), T ⁇ X-355 and UK- 427857, and a pharmaceutically acceptable carrier.
  • T-20 enfuvirtide
  • PRO 2000 PRO 542, PRO 140, AMD-3100, BMS-806, FP21399, GW873140
  • Schering C SCH-C
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, one, two, three, four, five or six HIV integrase inhibitors, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrag, or combination thereof, one, two, three or four HIV integrase inhibitors selected from the group consisting of S-1360, zintevir (AR-177), L-870812 and L-870810, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of fo ⁇ nula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrag, or combination thereof, one, two, three, four, five or six HIV budding/maturation inhibitors, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, PA- 457, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrag, or combination thereof, one, two or three second HIV protease inhibitors, one, two or three HIV reverese transcriptase inhibitors, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, one, two or three second HIV protease inhibitors selected from the group consisting of ritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684 and GW640385X, one, two or three HIV reverse transcriptase inhibitors selected from the group consisting of
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, one, two or three second HIV protease inhibitors, one, two or three HIV entry/fusion inhibitors, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formulae (I), (II), (III), (IN), (N), (NI) or (Nil), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrag, or combination thereof, one, two or three second HIN protease inhibitors selected from the group consisting of ritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, K ⁇ I-272, DPC-681, DPC-684 and GW640385X, one, two or three HIN entry/fusion inhibitors selected from the group consist
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IN), (N), (NI) or (Nil), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, one, two or three second HIN protease inhibitors, one, two or three HIN integrase inhibitors, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compoimd, or combination of compounds of formulae (I), (II), (III), (IN), (N), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrag, or combination thereof, one, two or three second HIV protease inhibitors selected from the group consisting of ritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, K ⁇ I-272, DPC-681, DPC-684 and GW640385X, one, two or three HIV integrase inhibitors selected
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrag, or combination thereof, one, two or three second HIV protease inhibitors, one, two or three HIN budding/maturation inhibitors, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formulae (I), (II), (III), (IN), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, one, two or three second HIV protease inhibitors selected from the group consisting of ritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684 and GW640385X, PA-457, and a pharmaceutically acceptable carrier.
  • the present invention provides a method of inhibiting the replication of an HIV virus comprising contacting said virus with a therapeuctially effective amount of a compound or combination of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pha ⁇ naceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrag, or combination thereof.
  • the present invention provides a method of inhibiting the replication of HIV comprising contacting said virus with any one of the pharmaceutical composition as disclosed hereinabove.
  • the present invention provides a method of treating or preventing an HIV infection comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrag, or combination thereof.
  • the present invention provides a method of treating or preventing an HIV infection comprising administering to a patient in need of such treatment any one of the pharmaceutical composition as disclosed hereinabove.
  • the present invention provides a method of inhibiting an HIV protease comprising contacting said HIV protease with a therapeuctially effective amount of a compound or combination of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof.
  • the present invention provides a method of inhibiting an HIV protease comprising contacting said protease with any one of the pharmaceutical compositions as disclosed hereinabove.
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991).
  • N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; sulfenyl groups such as phenylsulfenyl (phenyl-S-), triphenylmethylsulfenyl (trityl-S-) and the like; sulfinyl groups such as p- methylphenylsulfinyl (p-methylphenyl-S
  • Prefened N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • S and R configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
  • the compounds of the invention can comprise asymmetrically substituted carbon atoms.
  • all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the invention substantially free from their enantiomers or other diastereomers.
  • substantially free is meant greater than about 80% free of other enantiomers or diastereomers of the compound, more preferably greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95% free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound.
  • compounds comprising the possible geometric isomers of carbon-carbon double bonds and carbon-nitrogen double are also meant to be included in this invention.
  • stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill in the art. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers and then chromatographically separating the diastereomers and regeneration of the individual enantiomers, enzymatic resolution and the like.
  • Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions which do not cause racemization or inversion of stereochemistry at the chiral centers.
  • Diastereomeric mixtures of compounds resulting from a synthetic reaction can often be separated by chromatographic techniques which are well-known to those of ordinary skill in the art. Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC. Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliaries. The resulting diastereomers can then be separated by column chromatography.
  • any variable for example A, R, R l5 R2, R 3 , Rt, R 5 , R 6 , R7, R 8 , R9, Rio, R11, R12, R 13 , R 14 , R a , R b , R e , n, etc.
  • its definition on each occu ⁇ ence is independent of its definition at every other occu ⁇ ence.
  • combinations of substituents are permissible only if such combinations result in stable compounds.
  • Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
  • the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
  • These salts include but are not limited to the following: 4- acetamido-benzoate, acetate, adipate, alginate, carbonate, 4-chlorobenzenesulfonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, cholate, digluconate, cyclopentanepropionate, dichloroacetate, dodecylsulfate, ethanedisulfonate, ethanesulfonate, ethylsuccinate, formate, fumarate, galactarate, D- gluconate, D-glucuronate, glucoheptanoate, glutarate, lycerophosphate, glycolate, hemisulfate, heptanoate, hexan
  • the basic nitrogen-containing groups can be quatemized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
  • loweralkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides such
  • salts include salts with alkali metals or alkaline earth metals, such as aluminum, sodium, lithium, potassium, calcium, magnesium or zinc or with organic bases such as diethylethanolamine, diethanolamine, ethylenediamine, guanidine, meglumine, olamine (ethnolamine), piperazine, piperidine, triethylamine, tromethamine, benzathine, benzene- ethanamine, adenine, cytosine, diethylamine, glucosamine, guanine, nicotinamide, hydrabamine, tributylamine, deanol, epolamine or triethanolamine.
  • organic bases such as diethylethanolamine, diethanolamine, ethylenediamine, guanidine, meglumine, olamine (ethnolamine), piperazine, piperidine, triethylamine, tromethamine, benzathine, benzene- e
  • Represenative salts of the compounds of the present invention include, but not limited to, hydrochloride, methanesulfonate, sulfonate, phosphonate, isethionate and trifluoroacetate.
  • the compounds of the present invention can also be used in the form of prodrugs.
  • prodrugs include compounds wherein one, two or three hydroxy groups in the compound of this invention are functionalized with R 15 wherein R 15 is
  • Ri03 is C(Ri 05 )2, O or -N(R 105 );
  • R 10 is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl, each M is independently selected from the group consisting of H, Li, Na, K, Mg, Ca, Ba, -N(Ri 05 ) 2 , alkyl, alkenyl, and R 106 ; wherein 1 to 4-CH 2 radicals of the alkyl or alkenyl, other than the -CH 2 radical that is bound to Z, is optionally replaced by a heteroatom group selected from the group consisting of O, S, S(O), SO 2 and N(R 105 ); and wherein any hydrogen in said alkyl, alkenyl or R 106 is optionally replaced with a substituent selected from the group consisting of oxo, -OR 10 5, -R105, -N(R 105 ) 2 , -CN, -C(O)OR 105 , -C(O)N(
  • M' is H, alkyl, alkenyl or R 106 ; wherein 1 to 4 -CH 2 radicals of the alkyl or alkenyl is optionally replaced by a heteroatom group selected from O, S, S(O), SO 2 , or N(R 105 ); and wherein any hydrogen in said alkyl, alkenyl or Rioe is optionally replaced with a substituent selected from the group consisting of oxo, -OR 105 , -R105, -N(R ⁇ o 5 )2, -CN, -C(O)OR 105 , -C(O)N(R 105 ) 2 , -SO 2 N(R 105 ), -N(R ⁇ 05 )C(O)Rio 5 , -C(O)R 105 , -SR 105 , -S(O)R 105 , -SO 2 R 105 , -OCF 3 , -SR 106 , -SORio
  • component M or M' in the formulae set forth herein will have either a covalent, a covalent/zwitterionic, or an ionic association with either Z or R 103 depending upon the actual choice for M or M'.
  • M or M' is hydrogen, alkyl, alkenyl or R 106 , then M or M', is covalently bound to -R 103 or Z. If M is a mono or bivalent metal or other charged species (i.e.
  • prodrugs of the compoimd of the present invention serve to increase the solubility of these compounds in the gastrointestinal tract. These prodrags also serve to increase solubility for intravenous admimsfration of the compound.
  • prodrugs may be prepared by using conventional synthetic techniques. One of skill in the art would be well aware of conventional synthetic reagents to convert one or more of the hydroxy groups of the compounds of the present invention to a desired prodrug, functionalized by the substituents of formula (NIII) or (IX) as defined above.
  • the prodrugs of this invention are metabolized in vivo to provide the compound of this invention.
  • the compounds of the invention are useful for inliibiting retro viral protease, in particular HIN protease, in vitro or in vivo (especially in mammals and in particular in humans).
  • the compounds of the present invention are also useful for the inhibition of retrovirases in vivo, especially human immunodeficiency virus (HIN).
  • the compounds of the present invention are also useful for the treatment or prophylaxis of diseases caused by retrovirases, especially acquired immune deficiency syndrome or an HIN infection in a human or other mammal.
  • Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 20 mg/kg body weight daily.
  • Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drag combination, and the severity of the particular disease undergoing therapy.
  • the compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • Topical administration may also involve the use of transdermal adminisfration such as transdermal patches or iontophoresis devices.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection, or infusion techniques.
  • injectable preparations for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drag can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drag.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
  • inert diluent such as sucrose lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syraps, and elixirs containing inert diluents commonly used in the art, such as water.
  • compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • the compounds of the present invention can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically aceptable and metabolizable lipid capabale of forming liposomes can be used.
  • compositions in liposome form can contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the prefened lipids are the phospholipids and phosphatidyl cholines (lecithins), both natureal and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY. (1976), p. 33.
  • the compound of the invention can be administered as the sole active pharmaceutical agent, it can also be used in combination with one or more immimomodulators, antiviral agents, other antiinfective agents or vaccines.
  • antiviral agents to be administered in combination with a compound of the present invention include AL-721, beta interferon, polymannoacetate, reverse transcriptase inhibitors (for example, BCH-189, AzdU, carbovir, ddA, d4C, d4T (stavudine), 3TC (lamivudine) DP-AZT, FLT (fluorothymidine), BCH-189, 5-halo-3'-thia- dideoxycytidine, PMEA, bis-POMPMEA, zidovudine (AZT), MSA-300, trovirdine, R82193, L-697,661, BI-RG-587 (nevirapine), abacavir, zalcitabine, didanosine, tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIV-210, Racivir ( ⁇ -FTC), D-D4FC (Reverset,
  • agents that can be administered in combination with the compound of the present invention include HIV entry/fusion inhibitor (enfuvirtide (T-20), T- 1249, PRO 2000, PRO 542, PRO 140, AMD-3100, BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D (SCH-D), TNX-355, UK-427857and the like) and HIV budding/maturation inhibitor such as PA-457.
  • HIV entry/fusion inhibitor enfuvirtide (T-20), T- 1249, PRO 2000, PRO 542, PRO 140, AMD-3100, BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D (SCH-D), TNX-355, UK-427857and the like
  • PA-457 HIV entry/fusion inhibitor
  • Immunomodulators that can be administered in combination with the compound of the present invention include bropirimine, Ampligen, anti-human alpha interferon antibody, colony stimulting factor, CL246,738, Imreg-1, Imreg- 2, diethydithiocarbamate, interleukin-2, alpha-interferon, inosine pranobex, methionine enkephalin, murarnyl-tripeptide, TP-5, erythropoietin, naltrexone, tumor necrosis factor, beta interferon, gamma interferon, interleukin-3, interleukin-4, autologous CD 8+ infusion, alpha interferon immunoglobulin, IGF-1, anti- Leu-3A, auto vaccination, biostimulation, extracorporeal photophoresis, cyclosporin, rapamycin, FK-565, FK-506, G-CSF, GM-CSF, hyperthermia, isopinosine, IV
  • Any of a variety of HIV or AIDS vaccines for example, g ⁇ l20 (recombinant), Env 2-3 (g ⁇ l20), HIVAC-le (gpl20), gpl60 (recombinant), VaxSyn HIV-1 (g ⁇ l60), Immuno-Ag (gpl60), HGP-30, HIV- Immunogen, p24 (recombinant), VaxSyn HIV-1 (p24)
  • HIV or AIDS vaccines for example, g ⁇ l20 (recombinant), Env 2-3 (g ⁇ l20), HIVAC-le (gpl20), gpl60 (recombinant), VaxSyn HIV-1 (g ⁇ l60), Immuno-Ag (gpl60), HGP-30, HIV- Immunogen, p24 (recombinant), VaxSyn HIV-1 (p24)
  • HIV or AIDS vaccines
  • agents that can be used in combination with the compoimd of this invention are ansamycin LM 427, apurinic acid, ABPP, Al-721, carrisyn, AS-101, avarol, azimexon, colchicine, compound Q, CS-85, N- acetyl cysteine, (2-oxothiazolidine-4-carboxylate), D- pemcillamine, diphenylhydantoin, EL- 10, erythropoieten, flisidic acid, glucan, HPA-23, human growth hormone, hydroxchloroquine, iscador, L-ofloxacin or other quinolone antibiotics, lentinan, lithium carbonate, MM-1, monolaurin, MTP-PE, naltrexone, neurofropin, ozone, PAI, panax ginseng, pentofylline, pentoxifylline, Peptide T, pine cone extract, polymannoacetate,
  • agents that can be used in combination with the compound of this invention are antifungals such as amphotericin B, clotrimazole, flucytosine, fluconazole, ifraconazole, ketoconazole and nystatin and the like.
  • agents that can be used in combination with the compound of this invention are antibacterials such as amikacin sulfate, azithromycin, ciprofloxacin, tosufloxacin, clarithromycin, clofazimine, ethambutol, isoniazid, pyrazinamide, rifabutin, rifampin, streptomycin and TLC G-65 and the like.
  • anti-neoplasties such as alpha interferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD (methotrexate, bleomycin, doxorabicin, cyclophosphamide, vincristine and dexamethasone), PRO-MACE/MOPP (prednisone, methotrexate (w/leucovin rescue), doxorabicin, cyclophosphamide, taxol, etoposide/mechlorethamine, vincristine, prednisone and procarbazine), vincristine, vinblastine, angioinhibins, pentosan polysulfate, platelet factor 4 and SP-PG and the like.
  • COMP cyclophosphamide, vincristine, methotrexate and prednisone
  • etoposide mBACOD
  • mBACOD metal
  • agents that can be used in combination with the compound of this invention are drugs for treating neurological disease such as peptide T, ritalin, lithium, elavil, phenytoin, carbamazipine, mexitetine, heparin and cytosine arabinoside and the like.
  • agents that can be used in combination with the compound of this invention are anti-protozoals such as albendazole, azithromycin, clarithromycin, clindamycin, corticosteroids, dapsone, DIMP, eflornithine, 566C80, fansidar, furazolidone, L,671,329, letrazuril, metronidazole, paromycin, pefloxacin, pentamidine, piritrexim, primaquine, pyrimethamine, somatostatin, spiramycin, sulfadiazine, trimethoprim, TMP/SMX, trimetrexate and WR 6026 and the like.
  • anti-protozoals such as albendazole, azithromycin, clarithromycin, clindamycin, corticosteroids, dapsone, DIMP, eflornithine, 566C80, fansidar, furazolidone, L,671,329, letrazuril, met
  • a compound of this invention can be administered in combination with ritonavir.
  • a combination is especially useful for inhibiting HIV protease in a human.
  • Such a combination is also especially useful for inhibiting or treating an HIV infection in a human.
  • the compound of this invention and ritonavir can be administered as separate agents at the same or different times or they can be formulated as a single composition comprising both compounds.
  • ritonavir When administered in combination with a compound, or combination of compounds of this invention, ritonavir causes an improvement in the pharmacokinetics (i.e., increases half-life, increases the time to peak plasma concentration, increases blood levels) of the compound of this invention.
  • Another combination can comprise of a compound, or combination of compounds of the present invention with ritonavir and one or more reverse transcriptase inhibitors (for example, lamivudine, stavudine, zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIV-210, Racivir ( ⁇ -FTC), D-D4FC (Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz, capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC-083), DPC-961, MIV-150 TMC-120, TMC-125 and the like).
  • reverse transcriptase inhibitors for example, lamivudine, stavudine, zidovudine, abacavir,
  • Such a combination is useful for inhibiting or treating an HIV infection in a human.
  • the compound or combination of compounds of the present invention and ritonavir and one or more reverse transcriptase inhibitors can be administered as separate agents at the same or different times or they can be formulated as compositions comprising two or more of the compounds.
  • agents which can be combined with the compound of the present invention for the inhibition, treatment or prophylaxis of AIDS or an HIV infection are not limited to those listed above, but include in principle any agents useful for the treatment or prophylaxis of AIDS or an HIV infection.
  • the therapeutic agents When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.
  • the foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.
  • CPE Percent cytopathic effect
  • HIV-1 Resistant to ABT-378/r (A17) by In Vitro Passage MT4 cells (2xl0 6 ) were infected with pNL4-3 at an MOI of 0.03 for 2 h, washed, then cultured in the presence of ABT-378 and ritonavir at concentration ratio of 5: 1.
  • the concenfration of ABT-378 and ritonavir used in the initial passage was 1 nM and 0.2 nM respectively.
  • Viral replication was monitored by determination of p24 antigen levels in the culture supernatant (Abbott Laboratories), as well as by observation for any cytopathic effect (CPE) present in the cultures.
  • the viral supernatant was harvested for the proceeding passage. Following each passage, the drug concentrations in the subsequent passage were gradually increased. After 5 months of selection, 1.5 ⁇ M of ABT-378 can be used in the final passage.
  • the A17 virus was generated after 17 passages of pNL4-3 in the presence of ABT-378 and ritonavir at concentration ratio of 5:1.
  • compounds of the present invention exhibit EC 50 in the range of InM to l ⁇ M.
  • DMF is N,N-dimethylformamide
  • DMSO dimethylsulfoxide
  • THF is tetrahydrofuran
  • NMMO 4-methylmorpholine N-oxide
  • HOBT 1- hydroxybenzotriazole hydrate
  • DCC is 1,3-dicyclohexylcarbodiimide
  • EDAC is l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • DMAP is 4- (dimethylamino)pyridine
  • TFA is trifluoroacetic acid
  • DEPBT is 3- (diethoxyphosphoryloxy)-l,2,3-benzotriazin-4(3H)-one.
  • Compounds of fo ⁇ nula (2) can be deprotected with an acid (for example, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, aluminum chloride and the like) in an inert solvent (for example, dioxane, dichloromethane, chloroform, methanol, tetrahydrofuran, acetonitrile and the like) at a temperature from about 0°C to about room temperature, to provide (3).
  • an acid for example, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, aluminum chloride and the like
  • an inert solvent for example, dioxane, dichloromethane, chloroform, methanol, tetrahydrofuran, acetonitrile and the like
  • sulfonyl chlorides of formula (4) such as, but not limited to, 4-methoxybenzenesulfonyl chloride in the presence of an organic amine base (for example, triethylamine, diisobutylethyl amine, pyridine, and the like), at a temperature of about 25°C to about 80°C, in an inert solvent such as, but not limited to, dichloromethane, diethyl ether, tetrahydrofuran, chloroform, N,N-dimethylformamide, and the like, or mixtures thereof, give compounds of formula (5).
  • organic amine base for example, triethylamine, diisobutylethyl amine, pyridine, and the like
  • an inert solvent such as, but not limited to, dichloromethane, diethyl ether, tetrahydrofuran, chloroform, N,N-dimethylformamide, and the like, or mixtures thereof
  • Compounds of formula (5) can be deprotected to compounds of formula (6) using the conditions for the transformation of (2) to (3).
  • Compounds of formula (6) wherein IL t is 4-[hydroxyimino)methyl]phenyl can be obtained by (a) treating compounds of formula (2) with 4-(diacetoxymethyl)benzenesulfonyl chloride (7), (b) freating the product from step (a) with hydroxylamine, and (c) deprotection of the conesponding oxime of fo ⁇ nula (8).
  • compounds of formula (6) wherein t is 4- [hydroxyimino)methyl]phenyl can also be obtained by (a) freating compounds of formula (2) with 4-vinylbenzenesulfonyl chloride, (b) oxidation of the product of step (a) with an oxidizing agent such as, but not limited to, osmium tetroxide, in the presence of sodium metaperiodate to give aldehydes of formula (10), (c) treating compounds of formula (10) with hydroxylamine to give compounds of formula (8), and (d) deprotection of compounds of formula (8).
  • an oxidizing agent such as, but not limited to, osmium tetroxide
  • Amino acid esters of formula (11), wherein P 2 is lower alkyls (for example methyl, ethyl, tert-butyl and the like), can be treated with a suitably protected aldehyde of formula (12) (for example, P ⁇ 0 and Pn together with the nifrogen atom they are attached, form a phthahmido group) in the presence of a reducing agent under acidic conditions (for example, in the presence of acetic acid or hydrochloric acid) in an inert solvent, or mixture of solvents, such as methyl sulfoxide, methanol, dichloromethane, and the like, at a temperature of about room temperature to about 50°C, to provide compounds of formula (13).
  • a suitably protected aldehyde of formula (12) for example, P ⁇ 0 and Pn together with the nifrogen atom they are attached, form a phthahmido group
  • a reducing agent under acidic conditions
  • Examples of the reducing agent include, but are not limited to, sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydri.de, and BH 3 -pyridine. Removal of the phthahmido group can be achieved using hydrazine in a suitable solvent such as ethanol and the like, at a temperature of about room temperature to about 100°C, to provide compounds of formula (14).
  • Compounds of formula (14) can be converted to compounds of formula (15) by (a) treating compounds of formula (14) with an aldehyde having formula R 9 CHO, optionally in the presence of a drying agent (for example, magnesium sulfate, silica gel and the like) in an inert solvent, or mixture of solvents, such as dichloromethane, benzene, toluene, methanol, ethanol, methyl sulfoxide, and the like, at a temperature from about room temperature to about 100°C, and (b) reacting the product of step (a) with a reducing agent at about room temperature.
  • a drying agent for example, magnesium sulfate, silica gel and the like
  • solvents such as dichloromethane, benzene, toluene, methanol, ethanol, methyl sulfoxide, and the like
  • Examples of the reducing agent include, but are not limited to, sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, and BH 3 -pyridine.
  • the diamine of formula (15) can be treated with a carbonylating agent in an inert , solvent, or mixture of solvents, such as dichloromethane, 1,2 dichloroethane, toluene, acetonitrile, and the like, at a temperature of about room temperature to about 100°C, to provide compounds of formula (16).
  • Examples of the carbonylating agent include, but not are limited to, 4-nitrophenyl carbonate, phosphene, diphosgene, triphosgene, carbonyl diimidazole, disuccinimidyl carbonate.
  • Conversion of compounds of formula (16) to the conesponding acids having formula (17) can be achieved by acid hydrolysis (for example acetic acid, trifluoroacetic acid, toluenesulfonic acid, formic acid, hydrochloric acid and the like) or base hydrolysis (for example sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, and the like) in a solvent, or mixture of solvents such as N,N-dimethylformamide, toluene, benzene, dichloromethane, ethyl acetate, water, methanol and the like, at a temperature of about 0°C to about 100°C.
  • acid hydrolysis for example acetic acid, trifluoroacetic acid, tolu
  • Amino acid esters having formula (11), wherein P 2 is lower alkyls (for example, methyl, ethyl, tert-butyl and the like) can be treated with compounds of formula R 30 OC(O)CH 2 X, wherein R 30 is lower alkyls and X is Br, CI, or I, in an inert solvent, or mixture of solvents, such as N,N-dimethylformamide, dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, benzene, diethyl ether and the like, at a temperature of about room temperature to about 50°C, to provide (18).
  • an inert solvent or mixture of solvents, such as N,N-dimethylformamide, dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, benzene, diethyl ether and the like, at a temperature of about room temperature to about 50°
  • Compounds of formula (18) can be converted to compounds of fo ⁇ nula (19) by (a) treating with chlorosulfonyl isocyanate (or compounds of formula XSO 2 NCO, wherein X is Br, CI, or I, and the like) in an inert solvent, or mixture of solvents, such as dichloromethane, 1,2-dichloroethane, dioxane, toluene, N,N-dimethylformamide, tetrahydrofuran diethyl ether and the like, at a temperature of about -10°C to about room temperature, and (b) treating the product of step (a) with water at about room temperature.
  • chlorosulfonyl isocyanate or compounds of formula XSO 2 NCO, wherein X is Br, CI, or I, and the like
  • solvents such as dichloromethane, 1,2-dichloroethane, dioxane, toluene, N,N-dimethyl
  • (18) can be reacted with a carbonylating agent such as, but not are limited to, 4-nitrophenyl carbonate, phosphene, diphosgene, triphosgene, carbonyl diimidazole, disuccinimidyl carbonate, followed by reaction with ammonia.
  • a carbonylating agent such as, but not are limited to, 4-nitrophenyl carbonate, phosphene, diphosgene, triphosgene, carbonyl diimidazole, disuccinimidyl carbonate, followed by reaction with ammonia.
  • Cyclization of the compounds of formula (19) to provide compounds of formula (20) can be achieved be freating with an organic amine base such as triethyl amine, diisopropylethyl amine, imidazole, pyridine, N-methylmorpholine and the like, or an inorganic base such as sodium bicarbonate, sodium carbonate, cesium carbonate and the like, in an inert solvent, or mixture of solvents, such as methanol, ethanol, N,N- dimethylformamide, dioxane, xylene, tefrahydrofuran and the like, at a temperature of about room temperature to about 70°C.
  • an organic amine base such as triethyl amine, diisopropylethyl amine, imidazole, pyridine, N-methylmorpholine and the like
  • an inorganic base such as sodium bicarbonate, sodium carbonate, cesium carbonate and the like
  • solvents such as methanol, ethanol, N,
  • Imides of formula (20) can be converted to compounds of formula (22) by (a) deprotonation with a base in an inert solvent, or mixture of solvents, such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, and the like, at a temperature of about -78 to about 0°C, and (b) treating product of step (a) with an alkyl halide of formula (21), wherein X is CI, Br or I, at a temperature of about room temperature to about 100°C.
  • the base include, but are not limited to, sodium hydride, potassium hydride, lithium diisopropyl amide, lithium bis(trimethylsilyl)amide.
  • compounds of formula (20) can be converted to compounds of formula (22) by (a) deprotonation with a base in an inert solvent, or mixture of solvents, such as dichloromethane, 1,2-dich
  • Amino acid esters having formula (11) wherein P 2 is lower alkyls (for example, methyl, ethyl, tert-butyl and the like) can be treated with compounds such as, but not limited to, bis-(4-nifrophenyl)carbonate in an inert solvent, or mixture of solvents, such as N,N- dimethylformamide, dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, benzene, diethyl ether and the like at a temperature of about room temperature to about 50 °C, to provide (24).
  • compounds such as, but not limited to, bis-(4-nifrophenyl)carbonate in an inert solvent, or mixture of solvents, such as N,N- dimethylformamide, dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, benzene, diethyl ether and the like at a temperature
  • activating agent examples include, but are not limited to, l,r-carbonyldiimidazole (CDI), l,3-dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC), DEPBT (3- (diethoxyphosphoryloxy)-l,2,3-benzotriazin-4(3H)-one), PyBOP (benzotriazole- 1-yl-oxy- tris-pynolidinophosphonium hexafluorophosphate), and 1,3-di-tert-butylcarbodiimide.
  • CDI l,r-carbonyldiimidazole
  • DCC dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • EDAC dimethylaminopropyl)-3-eth
  • a salt or an activated ester derivative of acid (17) or (23) (for example, the acid chloride, prepared by reaction of the carboxylic acid with thionyl chloride in ethyl acetate or tefrahydrofuran or oxalyl chloride in toluene/N,N-dimethylformamide) can be reacted with (6).
  • compounds of formula (30) can be obtained by (a) treating compounds of formula (3) with compounds of formula (17) using the conditions for the transformation of compound of formula (6) to (30), and (b) treating the product from step (a) with a compound having fo ⁇ nula R SO 2 Cl, using the conditions for the transformation of compounds of formula (2) to compounds of formula (5).
  • purification means column chromatography using a silica gel column and eluting the column with a solvent system as specified in the experimental details.
  • Compounds of the invention were named by ACD/ChemSketch version 4.01 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or were given names consistent with ACD nomenclature.
  • Example 16 tert-butyl (1 S,2R 1 -benzyl-2-hydroxy-3- ⁇ isobutyl[(4- vinylphenyl)sulfonyl]amino ⁇ propylcarbamate
  • TEA triethylamine
  • EtOAc ethyl acetate
  • Example 17 ⁇ tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4- [hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propylcarbamate
  • Method A Part i tert-butyl ( 1 S,2R)- 1 -benzyl-3 - [ [(4-formylphenyl)sulfonyl] (isobutyl)amino] -2- hydroxypropylcarbamate
  • OsO solution 2.9 mL, 4% by weight in water
  • the solids formed was recrystallized by addition of about 2-3 volumes (relative to solid) of boiling ethyl acetate, followed by hexanes (2-3 volumes relative to ethyl acetate) until crystallization began. The mixture was kept at 25°C for 18 h, and the solids were filtered and washed with hexanes to give the product (14.38 g, 73%).
  • Example 18 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-[(E)-(hydroxyimino)methyl]-N- isobutylbenzenesulfonamide
  • a solution of Example 17 in dichloromethane (60 mL) was treated with 80% trifluoroacetic acid at 0°C for 3 h.
  • the solvents were evaporated, and the cis and trans oximes were treated with 5% trifluoroacetic acid in dichloromethane (20 mL) at 25 °C for 16 h.
  • the solvents were evaporated, and the residue was partitioned between ethyl acetate and IN NaHCO 3 .
  • Example 32 A (l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)acetaldehyde To a solution of phthalimide diethylacetal (15 g) in tetrahydrofuran (THF) (30 mL) was added 10%) aqueous HCI (18 mL). After heating at 75 °C for 5 hrs, the solution was allowed to cool to RT, and ethyl acetate (100 mL) was added. The solution was extracted with saturated sodium carbonate solution (100 mL), brine (100 mL), and the organic layer was separated and dried over magnesium sulfate (MgSO 4 ).
  • THF tetrahydrofuran
  • Example 32B tert-butyl (2S,3 S)-2- ⁇ [2-( 1 ,3-dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)ethyl] amino ⁇ -3- methylpentanoate
  • L-isoleucine tert-butyl ester hydrochloride 13.0 g, 58 mmol
  • sodium cyanoborohydride 7.3 g, 116 mmol
  • acetic acid 2mL
  • Example 32C tert-butyl (2S,3S)-2-[(2-aminoethyl)amino]-3-methylpentanoate
  • hydrazine hydrate (11.2 mL).
  • the solution was then heated to 70°C for 2 hrs. After cooling to 25°C, the resulting solid was dissolved in IN NaOH solution (200 mL) and water (200 mL).
  • the solution was then extracted with dichloromethane (3 x 200 mL), the organic exfracts combined, dried and evaporated to provide 6.8g of the title compound.
  • Example 32D tert-butyl (2S,3S)-3-methyl-2-[(2- ⁇ [(6-methyl-2- pyridinyl)methyl]amino ⁇ ethyl)amino]pentanoate 6-Methyl-2-pyridinecarboxaldehyde (4.25 g) was dissolved in dichloromethane (80 mL) and combined with Example 32C (8 g, 1 equivalent) and MgSO 4 (15 g), and the mixture was stined at 25°C for 2.5 hrs. The mixture wais filtered, rinsed with dichloromethane, and the solvents were evaporated. The residue was dissolved in methanol (80 mL) and treated with NaBH 4 at 0°C for 0.5 h.
  • Example 32E tert-butyl (2S,3S)-3-methyl-2- ⁇ 3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-l- imidazolidinyl ⁇ pentanoate
  • N,N-dimethylformamide 60 mL
  • bis-(p-nitrophenyl) carbonate 12.6 g, 1.2 equivalents
  • Example 32F (2S,3S)-3-methyl-2- ⁇ 3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-l-imidazolidinyl ⁇ pentanoic acid
  • Example 143 A 2- ⁇ [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] amino ⁇ ethanol 2-Methyl-4-(chloromethyl)thiazole (2.24 g) was treated with ethanolamine (11.6 mL, 10 equivalents) in dichloromethane at 25°C for 16 hrs. The solvent was evaporated and the residue partitioned between ethyl acetate and brine. The organic layer was separated and exfracted with ethyl acetate (5x). The organic layers were combined and washed with brine, dried over Na 2 SO 4 , and the solvents were evaporated to give 2.4 g (85%) of title compound.
  • Example 143B tert-butyl 2-hydroxyethyl[(2-methyl-l,3-thiazol-4-yl)methyl]carbamate
  • the product of Example 143A (2.4 g) was treated with di-t-butyl dicarbonate (2.85 g, 1 equivalent) in tefrahydrofuran/ IM NaHCO 3 (2:1) and stined at 25°C for 16 hrs.
  • the solvents were evaporated, and the residue was acidified with 10% citric acid and exfracted with ethyl acetate (3x).
  • the combined organic layer was washed with brine, dried over Na 2 SO 4 and evaporated.
  • the crude product was purified using 1% > methanol/dichloromethane to give 1.91 g (52%) of title compound.
  • Example 143C methyl (2S)-3-methyl-2-[(2- ⁇ [(2-methyl-l,3-thiazol-4- yl)methyl]amino ⁇ ethyl)amino]butanoate
  • oxalyl chloride 5.4 mL, 1.5 equivalents
  • DMSO 0.6 mL, 2 equivalents
  • triethylamine 4 mL, 4 equivalents
  • Example 143D (2 S)-3 -methyl-2- ⁇ 3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl ⁇ butanoic acid
  • a solution of the product of Example 143C (5.4 g) in tetrahydrofuran (80 mL) was treated with carbonydiimidazole (6.1 g, 2 equivalents) at 25°C for 2 hrs.
  • Example 148 A N-(2,2-dimethoxyethyl)-N-[(l-methyl-lH-benzimidazol-2-yl)methyl]amine
  • l-methyl-2-formylbenzimidazole (lg) in methanol (27 mL) and acetic acid (0.54 mL) was treated with aminoacetaldehyde diethylacetal (0.9 g, 1 equivalent) and NaCNBH 3 (0.85 g, 2 equivalents) at 25°C, stined for 1 hour.
  • the mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed sequentially with saturated NaHCO 3 and brine, and concentrated.
  • Example 148B 9H-fluoren-9-ylmethyl 2,2-dimethoxyethyl[(l-methyl-lH-benzimidazol-2- yl)methyl]carbamate
  • a solution of the product of Example 148 A (1.2 g) in dichloromethane (30 mL) was treated with 9-fluorenylmethyl succinimide (1.6 g, 1.05 equivalents) at 0°C for 16 hours. The mixture was partitioned between water and ethyl acetate.
  • Example 148C 9H-fluoren-9-ylmethyl (l-methyl-lH-benzimidazol-2-yl)methyl(2-oxoethyl)carbamate
  • a solution of the product of Example 148B (0.2 g) in tetrahydrofuran (0.2 mL) was treated with 30% HCI (0.2 mL), stined at 75°C for 6 hours, cooled to 25°C and concentrated. The residue was partitioned between 10% NaHCO 3 and ethyl acetate, the organic layer was separated and washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the title compound (175 mg).
  • Example 148D methyl (2S)-2-[(2- ⁇ [(9H-fluoren-9-ylmethoxy)carbonyl] [( 1 -methyl- 1 H-benzimidazol-2- yl)methyl]amino ⁇ ethyl)amino]-3,3-dimethylbutanoate
  • a solution of the product of Example 148C (0.178 g) and (L)-methyl t-leucinate hydrochloride (76.1 mg, 1 equivalent) in methanol (1.7 mL) and acetic acid (17 ⁇ L) was treated with NaCNBH 3 (54 mg, 2 equivalents) at 25°C for 3.5 hours. The mixture was partitioned between water and ethyl acetate.
  • Example 148E methyl (2S)-3,3-dimethyl-2- ⁇ 3-[(l-methyl-lH-benzimidazol-2-yl)methyl]-2- oxoimidazolidin-l-yl ⁇ butanoate
  • a solution of the product of Example 148D (0.19 g) in N,N-dimethylformamide (3.5 mL) was freated with diethylamine (0.35 mL), stined at 25°C for 1.5 hours and concentrated.
  • a solution of the residue in dichloroethane (7 mL) was treated with bis-(p-nifrophenyl) carbonate (0.128 g, 1.2 equivalents), stined at 60°C for 16 hours and concenfrated.
  • the residue was chromatographed on silica gel, eluting with ethyl acetate: dichloromethane (3:2) to give 80 mg (64%) of the title compound.
  • Example 148F (2S)-3 ,3-dimethyl-2- ⁇ 3- [( 1 -methyl- 1 H-benzimidazol-2-yl)methyl]-2-oxoimidazolidin- 1 - yl ⁇ butanoic acid
  • a solution of the product of Example 148E (37 mg) in tetrahydrofuran (0.26 mL) and water (0.13 mL) was treated with LiOH (6.1 mg, 1.4 equivalents), stined at 25°C for 16 hours, quenched with IN HCI (0.15 mL) at 0°C, and the solvents were evaporated to give the crude product to be used without further purification.
  • Example 159 (2S)-2-[3-( ⁇ 2-[(dimethylamino)methyl]-l,3-thiazol-4-yl ⁇ methyl)-2-oxo-l-imidazolidinyl]-3- methylbutanoic acid
  • Example 159A tert-butyl (2S)-2-[3-( ⁇ 2-[(dimethylamino)methyl]-l,3-thiazol-4-yl ⁇ methyl)-2-oxo-l- imidazolidinyl]-3-methylbutanoate
  • Example 273D (0.2 g, 0.54 mmol) was dissolved in toluene: ethanol (2.2 mL, 1:1) and treated with dimethylamine (0.54 mL, 2M in tetrahydrofuran, 2 equivalents) at 70 °C for 3 h.
  • the mixture was cooled to 25 °C and treated with sodium borohydride (20 mg, 3 equivalents) at 25 °C for 68 h.
  • the solvents were evaporated, and the crade residue was partitioned between ethyl acetate and saturated sodium bicarbonate.
  • the organic layer was separated, washed with brine, dried over magnesium sulfate, and the solvents were evaporated.
  • the crade residue was purified using ethyl acetate-ethyl acetate/10% methanol to give 0.11 g (53%o) of the title compound.
  • Example 159B (2S)-2-[3-( ⁇ 2-[(dimethylamino)methyl]-l,3-thiazol-4-yl ⁇ methyl)-2-oxo-l-imidazolidinyl]-3- methylbutanoic acid
  • Example 159A was dissolved in dichloromethane: trifluoroacetic acid (2.4 mL, 1 : 1) at
  • Example 160A N-(2,2-diethoxyethyl)-N-[(2-methyl-l,3-thiazol-4-yl)methyl]amine 4-Chloromethyl-2-methylthiazole (0.6 g, 4 mmol) was added to aminoacetaldehyde diethyl acetal (5 mL, 10 equivalents) dissolved in tetrahydrofuran (15 mL) at 25 °C, and the mixture was stined for 16 h. The solvents were evaporated and the excess aldehyde was distilled from the crade mixture. The crade residue was purified using dichloromethane - dichloromethane/ 10% methanol to give 0.76 g (76%) of the title compound.
  • Example 160B methyl (2S)-3-methyl-2- ⁇ 3-[(2-methyl-l,3-tl ⁇ iazol-4-yl)methyl]-2-oxo-2,3-dihydro-lH- imidazol- 1 -yl ⁇ butanoate
  • Example 160A (0.76 g, 3.1 mmol) was dissolved in tetrahydrofuran (12 mL) and treated with (L)-methyl valinate p-nitrophenylcarbamate (0.92 g, 1 equivalent), triethylamine (0.43 mL, 2 equivalents), and DMAP (60 mg, 1.5 equivalents) at 25 °C for 2 days.
  • the solvents were evaporated, and the crade residue was partitioned between ethyl acetate/10%) sodium carbonate, the organic layer was separated, dried over magnesium sulfate, and the solvents were evaporated.
  • the crade material was dissolved in formic acid (30 mL) at 25 °C for 16 h. the solvents were evaporated and the crade residue was purified using dichloromethane - ethyl actate to give 0.51 g (53%) of the title compound.
  • Example 160C Example 160B (0.1 g, 0.32 mmol) was dissolved in tefrahydrofuran:water (1.5 mL,
  • Example 146 (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2-(3- ⁇ [2-(methoxymethyl)- l,3-thiazol-4-yl]methyl ⁇ -2-oxoimidazolidin-l-yl)-3-methylbutanamide
  • Method A Example 146 (62 mg ) was combined with HOBT (39 mg, 1.5 equivalents) and EDAC (55 mg, 1.5 equivalents) in N,N-dimethylformamide (3 mL) and stined for 1 h at 25° C. To this mixture was added N-methylmorpholine (NMM) (42 ⁇ L, 2 equivalents) and Example 18 (80 mg, 1 equivalent).
  • NMM N-methylmorpholine
  • Example 162 (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3,3-dimethyl-2- ⁇ 3-[(l-methyl-lH- benzimidazol-2-yl)methyl] -2-oxoimidazolidin- 1 -yl ⁇ butanamide
  • Example 148F (36 mg) was dissolved in N,N-dimethylformamide (1.0 mL) and treated with Example 18 (44 mg, 1 equivalent), HOBT (14.4 mg, 1 equivalent), N- methylmorpholine (57 ⁇ L, 5 equivalents), and benzotriazole- 1-y 1-oxy-fris-py ⁇ olidino- phosphonium hexafluorophosphate (PyBOP) (54.6 mg, 1 equivalent) at 25°C for 16 hrs.
  • Example 270 (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxoimidazolidin-l-yl ⁇ butanamide
  • Example 756 (13 mg, 0.019 mmol) was dissolved in ethanol (0.5 mL) and treated with hydroxylamine hydrochloride (3.9 mg, 3 equivalents) for 3 hrs at 25°C. The solvents were evaporated, and the residue was purified using 8% methanol/dichloromethane to give 5 mg (38%>) ofthe title compound.
  • Example 271 (2,2-diethoxyethylidyne)- ⁇ 4 -sulfanylamine 1,1-Diethoxyacetamide (10 g, 0.068 mol) was dissolved in tefrahydrofuran (250 mL) and treated with P 4 S 10 (3 g, 0.1 eq) at 25 °C for 16 h. The solvents were evaporated and diluted with ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, and the solvents were evaporated to give 7.13 g (64%) of the crade product used directly for the next step.
  • Example 272 ethyl 2-(diethoxymethyl)-l,3-thiazole-4-carboxylate
  • Example 271 (7.13 g, 0.044 mol) was dissolved in ethanol (90 mL) and treated with ethyl bromopyravate (5.5 mL, 1 equivalent) and 3A molecular sieves (20 g) and the mixture was heated at 80 °C for 30 min. The mixture was filtered and the solvents were evaporated. The crade residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine and dried over magnesium sulfate.
  • Example 273A [2-(diethoxymethyl)- 1 ,3 -thiazol-4-yl]methanol
  • Example 273B 2-(diethoxymethyl)-l,3-tl ⁇ iazole-4-carbaldehyde
  • Example 272 (7.8 g, 30 mmol) was dissolved in toluene (60 mL) and treated with diisobutyl aluminum hydride (42 mL, 1.4 equivalents, IM in toluene) at -78 °C for 45 min. The mixture was quenched with ethyl acetate (50 mL) and warmed to 25 °C while adding sodium potassium tartrate (10 mL, 10%) for 2 h.
  • Example 273A was exfracted with ethyl acetate, the organic layer was washed with brine, dried over magnesium sulfate, and the solvents were evaporated.
  • Two products were purified using ethyl acetate: hexane (1:1) to give 0.8 g (10%) of Example 273 A and the remaining fractions consisted of crude Example 273B.
  • Example 273 C tert-butyl (2S)-2-(3 - ⁇ [2-(diethoxymethyl)- 1 ,3-thiazol-4-yl]methyl ⁇ -2-oxo- 1 -imidazolidinyl)- 3-methylbutanoate
  • Example 273B (0.144 g, 0.57 mmol) was dissolved in benzene: ethanol (3 mL, 1:1) treated with the valine analog of Example 32C (0.14 g, 1 equivalent) and the mixture was heated to 70 °C for 1 h. The mixture was cooled to 25 °C and treated with sodium borohydride (75 mg, 3 equivalents) for 2 h.
  • Example 273D tert-butyl (2S)-2- ⁇ 3-[(2-formyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo-l -imidazolidinyl ⁇ -3- methylbutanoate
  • Example 273C (0.1 g, 0.24 mmol) was dissolved in acetone (10 mL) and treated with IM HCI (1 mL) at 70 °C for 45 min. The solvents were evaporated and the crude residue was partitioned between ethyl acetate and saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and the solvents were evaporated to give 89 mg (99%) ofthe title compound.
  • Example 273E tert-butyl (2S)-3-methyl-2-[3-( ⁇ 2-[(methylamino)methyl]-l,3-thiazol-4-yl ⁇ methyl)-2-oxo-l- imidazolidinyl]butanoate
  • Example 273D (0.2 g, 0.54 mmol) was dissolved in toluene (1.1 mL) and ethanol (1.1 mL) and treated with methylamine solution in tetrahydrofuran (0.54 mL, 2M, 2 equivalents) and stined at 70 °C for' 3 h. The mixture was cooled to 25 °C and combined with sodium borohydride (20 mg, 3 equivalents) and stined for 18 h.
  • Example 273F tert-butyl (2S)-2- ⁇ 3-[(2- ⁇ [[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]methyl ⁇ -l,3- thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl ⁇ -3 -methylbutanoate
  • Example 273E (0.115 g, 0.3 mmol) was dissolved in dichloromethane (3 mL), cooled to 0 °C, combined with triethylamine (90 ⁇ L, 2.2 equivalents) and fluorenylmethyl chloroformate (86 mg, 1.1 equivalents).
  • Example 273G 9H-fluoren-9-ylmethyl ⁇ 4-[(3- ⁇ (lS)-l-[( ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hy ⁇ LxOxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ amino)carbonyl]-2- methylpropyl ⁇ -2-oxo-l-imidazolidinyl)methyl]-l,3-thiazol-2-yl ⁇ methyl(methyl)carbamate
  • Example 273F (10 mg, 0.017 mmol) was dissolved in trifluoroacetic acid: dichloromethane (1:1, 0.3 mL) at 25 °C for 90 min.
  • Example 273H (2S)-N- ⁇ (1 S,2R)- 1 -benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-methyl-2-[3-( ⁇ 2- [(methylamino)methyl]-l,3-thiazol-4-yl ⁇ methyl)-2-oxo-l-imidazolidinyl]butanamide
  • Example 273G (8 mg, 0.008 mmol) was dissolved in acetonitrile (0.1 mL) and treated with diethylamine (2 ⁇ L, 3 equivalents) at 25 °C for 1 h. The solvents were evaporated and the residue was purified using C-18 to give 6.5 mg (92%) ofthe title compound.
  • Example 274 (2S)-N- ⁇ (1 S,2R)- 1 -benzyl-2-hydroxy-3-[(
  • Example 274A (2R,3S)-3-amino-l-azido-4-phenylbutan-2-ol
  • (2R,3S)-3-N-tert-butoxycarbonylamino-l,2-epoxy-4-phenylbutane (1.17 g) in ethano water (45 mL, 4:1) was freated with lithium azide (1.09 g, 5 equivalents) and NH 4 C1 (1.19 g, 5 equivalents), stined at 75°C for 2 hours and concentrated.
  • the residue was partitioned between water and ethyl acetate.
  • the organic layer was separated, dried over MgSO 4 , filtered and concentrated.
  • a solution ofthe residue in dichloromethane/trifluoroacetic acid 40 mL, 1:1) was stined at 25°C for 1 hour and concenfrated to give the title compound.
  • Example 274B (2S)-N-[(lS,2R)-3-azido-l-benzyl-2-hydroxypropyl]-3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol- 4-yl)methyl]-2-oxoimidazolidin-l-yl ⁇ butanamide
  • EDAC 0.744 g, 1.2 equivalents
  • HOBT 0.65 g, 1.2 equivalents
  • N- methyl morpholine (0.88 mL, 2 equivalents
  • Example 143D (1.19 g, 1 equivalent)
  • stined 25°C for 1 hour and concentrated.
  • the residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%)) to give 1.3 g (67%) of title compound.
  • Example 274C (2S)-N-[(lS,2R)-3-amino-l-benzyl-2-hydroxypropyl]-3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol- 4-yl)methyl] -2-oxoimidazolidin- 1 -yl ⁇ butanamide
  • a solution ofthe product of Example 274B (1.3 g) in tetrahydrofuran: water (25 mL, 4:1) was treated with triphenylphosphine (1.4 g, 2 equivalents), stined at 70°C for 2 hours and concentrated. The residue was partitioned between IN HCI and dichloromethane.
  • Example 274D tert-butyl 2-[( ⁇ (2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxoimidazolidin-l-yl ⁇ butanoyl)amino]-4- phenylbutyl ⁇ amino)methyl]pynolidine- 1 -carboxylate
  • a solution ofthe product of Example 274C (59 mg) in ethano benzene (1 mL, 1:1) was treated with N-t-butoxylcarbonyl-(L)-prolinal (26 mg, 1 equivalent), stined at 70°C for 1 hour, cooled at 25°C, freated with NaBH 4 (14 mg, 3 equivalents) at 25°C and stined for 16 hours.
  • the mixture was quenched with saturated NH 4 C1 and partitioned between water and ethyl acetate. The
  • Example 274E tert-butyl 2-[(( ⁇ 4-[(hydroxyimino)methyl]phenyl ⁇ sulfonyl) ⁇ (2R,3S)-2-hydroxy-3-[((2S)-3- methyl-2- ⁇ 3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxoimidazolidin- 1 -yl ⁇ butanoyl)amino] -4- phenylbutyl ⁇ amino)methyl]pynolidine- 1 -carboxylate
  • a solution ofthe product of Example 274D (85 mg) in dichloromethane (0.6 mL) was treated with triethylamine (17 ⁇ L, 2 equivalents) and 4-formylbenzenesulfonyl chloride (12 mg, 1 equivalent), stined at 25°C for 2 hours and concentrated.
  • Example 274F (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(pynolidin-2-ylmethy l)amino]propyl ⁇ -3 -methyl-2- ⁇ 3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxoimidazolidin- 1 -yl ⁇ butanamide
  • a solution ofthe product of Example 274E (12 mg) in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) was stined at 25°C for 1 hour and concentrated. The residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%>) to give 10 mg (95%) ofthe title compound.
  • Example 275 (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxo-2,3-dihydro-lH-imidazol-l-yl ⁇ butanamide
  • Example 160C (62 mg, 0.22 mmol) was combined with HOBT (43 mg, 1.5 equivalents) and EDAC (60 mg, 1.5 equivalents) in N,N-dimethylformamide (3 mL) and stined for 1 hour at 25°C.
  • Example 18 (88 mg, 1.1 equivalents). The mixture was stined for 16 hours, evaporated, and chromatographed, eluting with 2.5% methanol/dichloromethane to give 60 mg (41%)) of title compound.
  • Example 276 (2S)-2-[3-(3-aminobenzyl)-2-oxoimidazolidin-l-yl]-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4- [(E)-(hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-methylbutanamide
  • Example 174 (68 mg, 0.09 mmol) was dissolved in ethyl acetate (1 mL) was freated with 10%) Pd/C (14 mg) for 2 h.
  • Example 278 (2S,3S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-methyl-2- ⁇ 3-[(l- oxidopyridin-4-yl)methyl]-2-oxoimidazolidin- 1 -yl ⁇ pentanamide
  • Example 181 (10.4 mg) was dissolved in tefrahydrofuran (0.25 mL) and treated with m-chloroperbenzoic acid (6 mg, 1.5 equivalents) at 25°C for 3 h. The solvents were evaporated, and the residue was purified using 7%> methanol/dichloromethane to give 10.5 mg (98%) ofthe title compound.
  • Example 279 (2S,3S)-2-(3- ⁇ [2-(aminomethyl)-l,3-thiazol-4-yl]methyl ⁇ -2-oxoimidazolidin-l-yl)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-methylpentanamide
  • Example 279A tert-butyl (2S,3S)-2-(3- ⁇ [2-(diethoxymethyl)-l,3-thiazol-4-yl]methyl ⁇ -2-oxo-l- imidazolidinyl)-3-methylpentanoate
  • Example 273B (0.86 g, 4 mmol) was dissolved in ethanol: benzene (12 mL, 1:1) and treated with Example 32C (0.55 g, 2.4 mmol) at
  • the mixture is cooled to 25 °C and freated with sodium borohydride (0.275 g, 3 equivalents) for 2 h.
  • the mixture is quenched with methanol and the solvents were evaporated.
  • the crude residue was dissolved in dichloroethane (100 mL) and freated with bis-p-nitrophenyl carbonate (0.9 g, 1.2eq) at 70 °C for 16 h.
  • the solvents were evaporated, and the crude residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate and the solvents were evaporated.
  • Example 279B tert-butyl (2S,3S)-2- ⁇ 3-[(2-formyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl ⁇ -3- methylpentanoate
  • Example 279A (0.72 g, 1.6 mmol) was dissolved in acetone (35 mL) and freated with IN HCI (3.5 mL) at 70 °C for 45 min.
  • Example 279C tert-butyl (2S,3S)-2-(3- ⁇ [2-(hydroxymethyl)-l,3-thiazol-4-yl]methyl ⁇ -2-oxo-l- imidazolidinyl)-3-methylpentanoate
  • Example 279B (0.2 g, 0.54 mmol) was dissolved in ethanol (5 mL) and treated with sodium borohydride (30 mg, 1.5 equivalents) and stined for 2 h. The solvents were evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer separated, washed with brine and dried over magnesium sulfate. The solvents were evaporated and the crade residue was used directly for the next reaction.
  • Example 279D tert-butyl (2S,3S)-3-methyl-2- ⁇ 3-[(2- ⁇ [(methylsulfonyl)oxy]methyl ⁇ -l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl ⁇ pentanoate
  • Example 279C (0.2 g, 0.3 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 °C, combined with triethylamine (0.22 mL, 3 equivalents) and methanesulfonyl chloride (0.06 mL, 1.5 equivalents). The mixture was stined at 0 °C for 90 min.
  • Example 279E tert-butyl (2S,3S)-2-(3- ⁇ [2-(azidomethyl)-l,3-thiazol-4-yl]methyl ⁇ -2-oxo-l-imidazolidinyl)- 3-methylpentanoate
  • Example 279D (0.25 g) was dissolved in dimethylformamide (4 mL) freated with lithium azide (0.255 g, 10 equivalents) and stined at 50 °C for 1 h. The solvents were evaporated and the residue was diluted with ethylacetate and washed with water, brine, and dried over magnesium sulfate. The solvents were evaporated to give 0.192 g crude azide.
  • Example 279F (2S,3S)-2-(3- ⁇ [2-( ⁇ [(9H-fluoren-9-ylmethoxy)carbonyl]amino ⁇ methyl)-l,3-thiazol-4- yl]methyl ⁇ -2-oxo- 1 -imidazolidinyl)-3-methylpentanoic acid
  • Example 279E (0.19 g, 0.47 mmol) was dissolved in tefrahydrofuran (4 mL) and water (1 mL) and treated with triphenylphosphine (0.247 g, 2 equivalents) and stined at 50 °C for 1 h.
  • the solvents were evaporated and the crade residue (0.127 g) was dissolved in acetonitrile (2.5 mL) and water (0.7 mL) and treated with sodium bicarbonate (67 mg, 2.4 equivalents) and fluorenylmethyl chloroformate (103 mg, 1.2 equivalents) and stined at 25 °C for 90 min.
  • the solvents were evaporated and the crade residue was diluted with ethyl acetate and washed with water, brine, dried over magnesium sulfate, and filtered.
  • the solvents were evaporated and the crude residue was purified using chloroform: ethyl acetate 4:1 - 1:1 to give 0.2 g (70%) ofthe ester. This ester was dissolved in dichloromethane: trifluoroacetic acid (5 mL, 3:2) and stined at 25 °C for 2 h. The solvents were evaporated to give 0.12 g ofthe title compound.
  • Example 279G (2S,3S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2- ⁇ 3-[(2- ⁇ [(9H-fluoren-9- ylmethyl)amino]methyl ⁇ - 1 ,3-thiazol-4-yl)methyl] -2-oxoimidazolidin- 1 -yl ⁇ -3- methylpentanamide
  • Example 279F (15 mg, 0.027 mmol) was dissolved in N,N-dimethylformamide (0.3 mL) and treated with EDAC (8 mg, 1.5 equivalents), HOBT (6 mg, 1.5 equivalents), N- methyl morpholine (7 ⁇ L, 2.5 equivalents), followed by Example 18 (17 mg, 1.5 equivalents) at 25°C for 16 hrs.
  • Example 279H (2S,3 S)-2-(3 - ⁇ [2-(aminomethyl)- 1 ,3-thiazol-4-yl]methyl ⁇ -2-oxo- 1 -imidazolidinyl)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-methylpentanamide
  • Example 279G (12 mg) was dissolved in acetonitrile (0.2 mL) and treated with diethylamine (3 ⁇ L, 3 equivalents) at 25°C for 2 h.
  • Example 280A 9H-fluoren-9-ylmethyl ⁇ 4-[(3- ⁇ (lS,2S)-l-[( ⁇ (lS,2R)-l-benzyl-3-[(cyclobutylmethyl)( ⁇ 4- [(E)-(hydroxyimino)methyl]phenyl ⁇ sulfonyl)amino]-2-hydroxypropyl ⁇ amino)carbonyl]-2- methylbutyl ⁇ -2-oxo-l-imidazolidinyl)methyl]-l,3-thiazol-2-yl ⁇ methylcarbamate
  • Example 280A was prepared using Example 279F (15 mg, 0.027mmol), N-methyl morpholine (7 ⁇ L, 2.5 equivalents), HOBT (6 mg, 1.5 equivalents), EDAC (8 mg, 1.5 equivalents) and Example 19 (18 mg, 1.5 equivalents) in dimethylfomamide (0.3 mL) to give 11.8 mg (46%>) after purification on C-18
  • Example 280B 9H-fluoren-9-ylmethyl ⁇ 4-[(3- ⁇ (lS,2S)-l-[( ⁇ (lS,2R)-l-benzyl-3-[(cyclobutylmethyl)( ⁇ 4- [(E)-(hydroxyimino)methyl]phenyl ⁇ sulfonyl)amino]-2-hydroxypropyl ⁇ amino)carbonyl]-2- methylbutyl ⁇ -2-oxo-l-imidazolidinyl)methyl]-l,3-thiazol-2-yl ⁇ methylcarbamate
  • Example 280A 11 mg, 0.013 mmol was treated with diethylamine (3 ⁇ L).
  • Example 281 (2S,3S)-2-(3- ⁇ [2-(aminomethyl)-l,3-thiazol-4-yl]methyl ⁇ -2-oxo-l-imidazolidinyl)-N- ⁇ (lS,2R)-l-benzyl-3-[(cyclopentyhnethyl)( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)amino]-2-hydroxypropyl ⁇ -3-methyl ⁇ entanamide
  • Example 281 was prepared using Example 279F
  • Example 27 (91 mg, 1.5 equivalents) in dimethylfomamide (1.2 mL) to give 79.5 mg (60%) after purification on C-18 using 75%> water/0. l%trifiuoroacetic acid /25%> acetonitrile - 100% acetonitrile.
  • This product was treated with diethylamine (20 ⁇ L, 3 equivalents) as in Example 279H. The crude product was purified by C-18 using 95% water/0. l%trifluoroacetic acid /5% acetonitrile - 100% acetonitrile to give 49 mg (70%) ofthe title compound.
  • Example 282 (2S,3S)-N- ⁇ (1 S,2R)-1 -benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2-[3-( ⁇ 2-[N- hydroxyethanimidoyl]pyridin-4-yl ⁇ methyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl]-3- methylpentanamide
  • Example 405 (30 mg, 0.039 mmol) was dissolved in ethanol (1 mL) and freated with NaBH 4 (7 mg, 5 equivalents) at 25°C for 16 hrs.
  • a solution of Example 273D (65 mg) in toluene: ethanol (0.7 mL, 1:1) was treated with isopropylamine (0.14 mL, 10 equivalents), stined at 70°C in a capped vial for 2 hrs. The mixture was cooled to 25°C and NaBH 4 (19 mg, 3 equivalents) was added and the mixture was stined at 25°C for 3 days.
  • Example 283B (2S,3S)-2- ⁇ 3-[(2- ⁇ [[(9H-fluoren-9-ylmethoxy)carbonyl](isopropyl)amino]methyl ⁇ -l,3- , thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl ⁇ -3-methylpentanoic acid
  • a solution ofthe product of Example 283A (59 mg) in acetonitrile (0.9 mL) and water (0.3 mL) was treated with NaHCO 3 (34 mg, 2.4 equivalents) followed by 9-fluorenylmethyl chloroformate (53 mg, 1.2 equivalents) at 25°C for 1.5 h.
  • Example 283C 9H-fluoren-9-ylmethyl ⁇ 4-[(3- ⁇ (1 S,2S)-l-[( ⁇ (1 S,2R)- 1 -benzyl-3-[(cyclopentylmethyl)( ⁇ 4- [(E)-(hydroxyimino)methyl]phenyl ⁇ sulfonyl)amino]-2 -hydroxypropyl ⁇ amino)carbonyl]-2- methylbutyl ⁇ -2-oxo-l-imidazolidinyl)methyl]-l,3-thiazol-2-yl ⁇ methyl(isopropyl)carbamate
  • EDAC 16 mg, 1.2 equivalents
  • HOBT 11 mg, 1.2 equivalents
  • N- methylmo ⁇ holine 18 ⁇ L, 2.4 equivalents
  • Example 284 (2R,3R)-N- ⁇ (lS,2R)-l-benzyl-3-[(cyclopentylmethyl)( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)amino]-2-hydroxypropyl ⁇ -2-[3-( ⁇ 2- [(isopropylamino)methyl] - 1 ,3 -thiazol-4-yl ⁇ methyl)-2-oxo- 1 -imidazolidinyl] -3 - methylpentanamide
  • a solution of Example 283C (38.5 mg, 0.038 mmol) in acetonitrile (0.5 mL) and diethylamine (9 ⁇ L, 3 equivalents) was stined at 25°C for 1 h.
  • Example 283D The solvents were evaporated and the residue was purified by HPLC reverse phase chromatography using water (0.1 %> trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%>) to give 30.9 mg of amines.
  • the two products were separated by preparative TLC using 0.5 mm silica gel plates, eluting with 5% methanol/chloroform/0.2%) ammomum hydroxide to give 7.3 mg of Example 283D and 7.4 mg of Example 284.
  • Example 285 (2S,3S)-2-(3- ⁇ 3-[amino(hydroxyimino)methyl]benzyl ⁇ -2-oxo-l-imidazolidinyl)-N- ⁇ (lS,2R)- l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-methylpentanamide
  • Example 201 (65 mg) was dissolved in ethanol (1 mL) and freated with triethylamine (0.13 mL, 10 equivalents) and hydroxylamine hydrochloride (25 mg, 4 equivalents) at 50°C for 6 h.
  • Example 286A 6-[(trityloxy)methyl]pyridine-2-carbaldehyde 2,6-Dimethanol pyridine (1 g) was prepared per J. Org. Chem. 63, 3884-3894 (1998) to give 330 mg (12%>) ofthe mono-trityl analog.
  • the trityl ether (0.33 g) was dissolved in dichloromethane (2 mL) and stined at 25°C with manganese dioxide (0.5 g, 7 equivalents) for 3 days. The mixture was filtered through Celite ⁇ , and purified using dichloromethane to give 0.284 g (86%) ofthe title compound.
  • Example 286B tert-butyl (2S,3S)-3-methyl-2-[2-oxo-3-( ⁇ 6-[(frityloxy)methyl]pyridin-2- yl ⁇ methyl)imidazolidin-l-yl]pentanoate
  • a solution ofthe product of Example 286A (0.28 g) in dichloromethane (5 mL) was treated with Example 32C (0.17 g, 1 equivalent) and MgSO (1 g) and the mixture was stined at 25°C for 2 h. The mixture was filtered and the solvents were evaporated. The residue was dissolved in methanol (5 mL) and treated withNaBH (42 mg, 1.5 equivalents) at 25°C for 1 h.
  • the mixture was partitioned between water and ethyl acetate, the organic layer was separated and dreid over Na 2 SO 4 , filtered and the solvents were evaporated. The residue was used directly for the next step.
  • the crude diamine was dissolved in N,N-dimethylformamide (15 mL) and treated with bis-(p-nifrophenylcarbonate (0.27 g, 1.2 equivalents) at 50°C for 3 h.
  • the mixture was partitioned between water and ethyl acetate and the organic layer was separated, washed with saturated NaHCO 3 , dried over NaSO , filtered and the solvents were evaporated.
  • the residue was purified using 5% ethyl acetate in dichloromethane to give 0.35 g (76%) ofthe title compound.
  • Example 286C (2S ,3 S)-3 -methyl-2- [2-oxo-3 -( ⁇ 6- [(trityloxy)methyl]pyridin-2-yl ⁇ methyl)imidazolidin- 1 - yfjpentanoic acid
  • a solution ofthe product of Example 286B (0.35 g) in trifluoroacetic acid: dichloromethane (3 mL, 2:1) was stined at 25°C for 2 hrs. The solvents were evaporated and the residue was directly used for the next step.
  • Example 286D (2S,3S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3 -methyl-2- [2-oxo-3-( ⁇ 6- [(trityloxy)methyl]pyridin-2-yl ⁇ methyl)imidazolidin-l-yl]pentanamide
  • EDAC 0.17 g, 1.5 equivalents
  • HOBT HOBT
  • N-methylmorpholine (0.13 mL, 2 equivalents) followed by the Example 18 (0.27 g, 1.1 equivalents).
  • Example 286E (2S,3S)-N- ⁇ (1 S,2R)- 1 -benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2-(3 - ⁇ [6- (hydroxymethyl)pyridin-2-yl]methyl ⁇ -2-oxoimidazolidin- 1 -yl)-3-methylpentanamide
  • a solution ofthe product of Example 286D (0.166 g) in methanol: dichloromethane (2 mL, 3:2) at 0°C was treated with concenfrated HCI (1 mL).
  • Example 287 (2S,3S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2-[3-( ⁇ 6- [(hydroxyimino)methyl]-2-pyridinyl ⁇ methyl)-2-oxo-l-imidazolidinyl]-2,3- dimethylpentanamide
  • Example 286E (10 mg, 0.014 mmol) was dissolved in dichloromethane (50 mL) and treated with MnO 2 (72 mg, 50 equivalents) at 25°C for 16 hrs.
  • Example 288A (2S)-2- ⁇ 3-[(6-acetyl-2- ⁇ yridinyl)methyl]-2-oxo-l-imidazolidinyl ⁇ -N- ⁇ (lS,2R)-l-benzyl-2- hydroxy-3-[( ⁇ 4-[(E)-(hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3,3- dimethylbutanamide
  • Example 122 (0.17 g) was dissolved in N,N-dimethylformamide (2 mL) and treated with EDAC (0.19 g, 2.7 equivalents), HOBT (0.134 g, 2.7 equivalents), N-methylmorpholine (88 ⁇ L, 2.1 equivalents) and Example 18 (0.28 g, 1.78 equivalents) at 25°C for 2.5 days.
  • Example 288B (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2-(3 - ⁇ [6-(l - hydroxyethyl)pyridin-2-yl]methyl ⁇ -2-oxoimidazolidin-l-yl)-3,3-dimethylbutanamide
  • a solution ofthe product of Example 288A (86 mg) in methanol (1.5 mL) was treated with NaBH (8.8 mg, 2 equivalents) at 0°C.
  • the reaction was filtered to remove solid salts, and the filtrate was treated with triethylamine (9.3 mL, 67.0 mmol) and ethyl bromoacetate (9.9 mL, 67.0 mmol), and the reaction was stined for 3 h at 25 °C.
  • the reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO 4 , filtered and evaporated to give 5.7 g (93%) ofthe product which was used without further purification.
  • Example 289B tert-butyl (2S,3S)-2-[(aminocarbonyl)(2-ethoxy-2-oxoethyl)amino]-3-methylpentanoate
  • dichloromethane 60 mL
  • chlorosulfonyl isocyanate 2.7 mL, 31.0 mmol
  • Water 60 mL was added to the cold reaction and the mixture was warmed to room temperature and stined for 4 h.
  • the reaction was partitioned between dichloromethane and water, and the organic was washed with brine and dried over MgSO 4 , filtered and evaporated to give 6.83 g ofthe product which was used without further purification.
  • Example 289C tert-butyl (2S,3S)-2-(2,4-dioxo-l-imidazolidinyl)-3-methylpentanoate
  • methanol 30 mL
  • triethylamine 5.6 mL, 40.2 mmol
  • the solvent was evaporated and the residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with 30%> ethyl acetate in dichloromethane to give 2.53 g (47%) ofthe title compound
  • Example 289D tert-butyl (2S,3S)-3-methyl-2- ⁇ 3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-l- imidazolidinyl ⁇ pentanoate
  • 6-methyl-2-pyridinemethanol 0.053 mg, 0.435 mmol
  • triphenylphosphine 0.135 g, 0.515 mmol
  • diethyl azodicarboxylate 0.080 mL, 0.515 mmol
  • Example 289E (2S,3S)-3-methyl-2- ⁇ 3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-l-imidazolidinyl ⁇ pentanoic acid
  • dichloromethane 3 mL
  • trifluoracetic acid 3 mL
  • Example 290 (2S)-2- ⁇ 3-[(2-ethyl-l ,3-thiazol-4-yl)methyl]-2,4-dioxo- 1 -imidazolidinyl ⁇ -3-methylbutanoic acid
  • Example 290A tert-butyl (2S)-2-[(2-ethoxy-2-oxoethyl)amino]-3-methylbutanoate
  • To a solution of (L)-valine tert-butyl ester hydrochloride (4.94 g, 23.6 mmol) in N,N- dimethylformamide (55 mL) was added triethylamine (3.28 mL, 1 equivalent), and the mixture was stined for 1 h.
  • the reaction was filtered to remove solid salts, and the filtrate was freated with triethylamine (9.85 mL, 3 equivalents) and ethyl bromoacetate (7.84 mL, 3 equivalents), and the reaction was stined for 3 h at 25 °C.
  • the reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO 4 , filtered and evaporated to give 4.48 g (78%>) ofthe product which was used without further purification.
  • Example 290B tert-butyl (2S)-2-[(aminocarbonyl)(2-ethoxy-2-oxoethyl)amino]-3-methylbutanoate
  • Example 290A (4.48 g, 18.3 mmol) was dissolved in dichloromethane (30 mL) at 0 °C and was treated with chlorosulfonyl isocyanate (2.07 mL, 1.3 equivalents) and the mixture was stined at 0 °C for 16 h. Water (60 mL) was added to the cold reaction and the mixture was warmed to 25 °C and stined for 4 h. The reaction was partitioned between dichloromethane and water, and the organic was washed with brine and dried over MgSO 4 , filtered and evaporated to give crade product which was used without further purification.
  • Example 290C tert-butyl (2S)-2-(2,4-dioxo-l-imidazolidinyl)-3-methylbutanoate
  • Example 290B (crade product) was dissolved in methanol (30 mL) and was treated with triethylamine (5.07 mL, 2 equivalents), and the mixture was stined at 50 °C for 2 h. The solvent was evaporated and the residue was purified using dichloromethane (100%>) - 25%> ethyl acetate/dichloromethane to give 2.97 g (63%>) ofthe title compound.
  • Example 290D tert-butyl (2S)-2- ⁇ 3-[(2-ethyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl ⁇ -3- methylbutanoate
  • Example 290C (0.076 g, 0.297 mmol) was dissolved in N,N-dimethylfo ⁇ namide (1.5 mL) at 0 °C and treated with sodium hexamethyldisilazide (0.33 mL, 1.1 equivalents, IM in tetrahydrofuran) and the mixture is stined for 1 h.
  • Example 290E (2S)-2- ⁇ 3-[(2-ethyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl ⁇ -3-methylbutanoic acid
  • Example 290E (75 mg, 0.196 mmol) was dissolved in dichloromethane (1 mL) and trifluoracetic acid (1 mL), and the mixture was stined at room temperature for 1 h. The solvent was evaporated and the crade product was used directly for coupling procedures.
  • Example 361 A tert-butyl (2S)-2-(3- ⁇ [2-(diethoxymethyl)-l,3-thiazol-4-yl]methyl ⁇ -2,4-dioxo-l- imidazolidinyl)-3-methylbutanoate
  • Example 290C 25 mg, 0.098 mmol
  • Example 273 A (21.2 mg, 1 equivalent), triphenylphosphine (31 mg, 1.2 equivalents), and diethyldiazodicarboxylate (18.2 ⁇ L, 1.2 equivalents)
  • the mixture was stined at 25 °C for 1 h, quenche with water, the organic layer was separated, dried over magnesium sulfate, filtered, and the solvents were evaporated.
  • the crade residue was purified using dichloromethane (100%) - 20% ethyl acetate/dichloromethane to give 28 mg (63%) ofthe title compound.
  • Example 36 IB tert-butyl (2S)-2- ⁇ 3-[(2-formyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl ⁇ -3- methylbutanoate
  • Example 361 A (0.31 g, 0.68 mmol) was dissolved in acetone (14 mL) and IM HCI (1.4 mL) and heated to 70 °C for 1 h.
  • Example 36 IC tert-butyl (2S)-2-[3-( ⁇ 2-[(dimethylamino)methyl]-l,3-thiazol-4-yl ⁇ methyl)-2,4-dioxo-l- imidazolidinyl]-3-methylbutanoate
  • Example 361B (0.12 g, 0.31 mmol) was dissolved in ethanol: benzene (1.2 mL, 1:1) and treated with dimethylamine (0.79 mL, 2M in tefrahydrofuran) and heated to 70 °C for 2 h.
  • the mixture was cooled to 25 °C and treated with sodium cyanoborohydride (39.5 mg, 2 equivalents) and acetic acid (90 ⁇ L, 5 equivalents) and the reaction was quenched by saturated ammonium chloride after 1 h.
  • the mixture was partitioned between water and ethyl acetate, the organic layer was separated, washed with brine, dried over magnesium sulfate and the solvents were eveaporated.
  • the crade residue was purified using dichloromethane (100%) - 4% methanol/dichloromethane to give 63 mg (49%) ofthe title compound.
  • Example 361D (2S)-2-[3-( ⁇ 2-[(dimethylamino)methyl]- 1 ,3-thiazol-4-yl ⁇ methyl)-2,4-dioxo- 1 - imidazolidinyl] -3 -methylbutanoic acid
  • Example 361C (52 mg, 0.127 mmol) was dissolved in trifluoroacetic acid dichloromethane (2 mL, 1:1) at 25 °C for 1 h. The solvents were evaporated to give the crude acid trifluoroacetic acid salt.
  • Example 294 (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2-(3- ⁇ [2-(methoxymethyl)- l,3-thiazol-4-yl]methyl ⁇ -2,4-dioxo-l-imidazolidinyl)-3-methylbutanamide
  • Example 294 (47 mg) is combined with HOBT (28 mg, 1.5 equivalent) and EDAC (32 mg, 1.5 equivalents) in N,N-dimethylformamide (1 mL) and stined for 1 h at 25° C. To this mixture is added N-methylmorpholine (NMM) (30 ⁇ L, 2 equivalents) and Example 18 (57 mg, 1 equivalent).
  • NMM N-methylmorpholine
  • Example 401 (2S)-2-[3-(3-aminobenzyl)-2,4-dioxo-l-imidazolidinyl]-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3- [( ⁇ 4-[(E)-(hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3- methylbutanamide
  • Example 363 (75 mg) was dissolved in ethyl acetate (1 mL) and combined with 10% > Pd/C (30 mg), a hydrogen balloon, and stined at 25 °C for 2 h. The mixture was filtered, and the solvents were evaporated. The residue was purified using 2% methanol/CHCl 3 to give 45 mg (63%) ofthe title compound.
  • Example 402 (2S)-N- ⁇ (1 S,2R)- 1 -benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2-(3- ⁇ 3-[N- hydroxyethanimidoyl]benzyl ⁇ -2,4-dioxo-l-imidazolidinyl)-3-methylbutanamide
  • Example 376 (90 mg, 0.12 mmol) was dissolved in ethanol (2 mL) and freated with hydroxylamine hydrochloride (34 mg, 4 equivalents) and triethylamine (0.17 mL, 10 equivalents) at 50 °C for 3 h.
  • Example 403 (2S)-2- ⁇ 3-[3-(aminomethyl)benzyl]-2,4-dioxo-l -imidazolidinyl ⁇ -N- ⁇ (1 S,2R)-1 -benzyl-2- hydroxy-3-[( ⁇ 4-[(E)-(hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3- methylbutanamide
  • Example 382 (10 mg, 0.013 mmol) was dissolved in ethyl acetate (0.5 mL) and combined with Lindlar's catalyst (6 mg) and a hydrogen balloon and stined for 2 h. The mixture was filtered, and the solvents were evaporated. The residue was purified on florasil using 10% methanol/dichloromethane to give 5 mg (50%) ofthe title compound.
  • Example 405 (2S,3S)-N- ⁇ (1 S,2R)- 1 -benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2-[3-( ⁇ 2-[N- hydroxyethanimidoyl]-4-pyridinyl ⁇ methyl)-2,4-dioxo-l-imidazolidinyl]-3- methylpentanamide
  • Example 381 (20 mg, 0.026 mmol) was dissolved in ethanol (0.3 mL) and treated with hydroxylamine hydrochloride (7 mg, 4 equivalents) and triethylamine (37 ⁇ L, 10 equivalents) at 50 °C for 6 h.
  • Example 406 methyl (2S,3S)-3-methyl-2- ⁇ [(4-nifrophenoxy)carbonyl]amino ⁇ pentanoate
  • (L)-methyl wo-leucinate hydrochloride 2.5 g, 13.75 mmol
  • dichloromethane 35 mL
  • 4-nifrophenyl chloroformate 3.05, 15.13 mmol
  • N-methylmorpholine 3.2 mL, 29.11 mmol
  • Example 407 methyl (2S)-3-methyl-2- ⁇ [(4-nifrophenoxy)carbonyl]amino ⁇ butanoate ( )-Methyl valinate (1 g) was dissolved in dichloromethane (10 mL) and freated with bis-(4-nitrophenyl) carbonate (1.2 g, 1.1 equivalents) and N-methylmorpholine(1.5 mL, 2.5 equivalents) at 0 °C for 4 h. The reaction was quenched with IM NaHCO 3 , and the organic layer was separated, washed with brine, dried with Na 2 SO 4 , filtered, and evaporated. The residue is purified using ethyl acetate/hexanes (2:3) to give 1.65 g (96%) ofthe title compound.
  • Example 408A N-methyl(2-methyl-l,3-thiazol-4-yl)methanamine 2-Methyl-4-(chloromethyl)thiazole (2.94 g, CAS#39238-07-8) was dissolved in 40% methylamine (39 mL, 25 equivalents) at 25 °C for 1 h. The mixture was evaporated and purified using 10%> methanol/dichloromethane with 0.5% ⁇ H 4 OH to give 2.83 g (99%) ofthe amine.
  • Example 408B methyl (2S)-3-methyl-2-[( ⁇ methyl[(2-methyl-l ,3-thiazol-4- yl)methyl] amino ⁇ carbonyl)amino]butanoate
  • Example 408A (2.83 g) was dissolved in tefrahydrofuran (80 mL) and freated with triethyl amine (2.8 mL, 1 equivalent), DMAP (0.28 g, 0.02 equivalent), and Example 407 (5.9 g, 1 equivalent) at 25 °C for 16 h. The mixture was quenched with 10%> K 2 CO 3 , and the organic layer was separated, dried with Na2SO4, filtered, and evaporated to give the crude thiazole ester which was used directly in the next step.
  • Example 408C (2S)-3-methyl-2-[( ⁇ methyl[(2-methyl-l,3-thiazol-4- yl)methyl]ammo ⁇ carbonyl)amino]butanoic acid
  • Example 408B (0.57 g) was dissolved in dioxane (8 mL) and freated with 1.4M LiOH (8 mL, in water) at 25 °C for 1 h. The mixture was quenched with iM HCI (4 mL), and the solvents were evaporated, and the residue was purified using 5% methanol/dichloromethane to give 0.52 g (96%) ofthe acid.
  • Example 434 (2S,3S)-N- ⁇ (1S,2R)- 1 -benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-methyl-2-( ⁇ [methyl(2- pyridinylmethyl)amino]carbonyl ⁇ amino)pentanamide
  • Method A (20 mg, 0.071 mmol ) is combined with HOBT (9.6 mg, 1.5 equivalent) and EDAC (14 mg, 1.5 equivalents) in N,N-dimethylformamide (1 mL) and stined for 1 h at 25° C.
  • NMM N-methylmorpholine
  • Example 18 (20 mg, 1 equivalent).
  • the mixture is stined for 16 h, evaporated under vacuum, and purified by silica gel chromatography using 7% methanol/dichloromethane to give 13.4 mg (41%) ofthe title compound.
  • Example 435 (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2-( ⁇ [[(2-isopropyl- 1 ,3 - thiazol-4-yl)methyl](methyl)amino]carbonyl ⁇ amino)-3-methylbutanamide Method ⁇
  • Example 409 (activated as O-succinimide ester) (75 mg, 0.18 mmol) was dissolved in dichloromethane (1 mL) and ⁇ , ⁇ -dimethylformamide (0.5 mL) and freated with Example 18 (85 mg, 1.1 equivalents) and N-methylmorpholine(24.3 ⁇ L, 1.2 equivalents) at 25 °C for 16 h.
  • Example 466 (2S,3R)-N- ⁇ (lS,2R)-l-benzyl-3-[(cyclobutylmethyl)( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)amino]-2-hydroxypropyl ⁇ -3-hydroxy-2-( ⁇ [ ⁇ [2- (methoxymethyl)- 1 ,3-thiazol-4-yl]methyl ⁇ (methyl)amino]carbonyl ⁇ amino)butanamide
  • Example 444 (57 mg, 0.073 mmol) was freated with trifluoroacetic acid: dichloromethane (4 mL, 1 :1) at 25 °C for 1 h. The solvents were evaporated and the crude solid was triturated with ethyl acetate: hexanes 1:5 to give 53 mg (99%) ofthe title compound.
  • Example 467 (2S,3R)-N- ⁇ (lS,2R)-l-benzyl-3-[(cyclopentyhnethyl)( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)amino]-2-hydroxypropyl ⁇ -3-hydroxy-2-( ⁇ [ ⁇ [2- (methoxymethyl)-l,3-thiazol-4-yl]methyl ⁇ (methyl)amino]carbonyl ⁇ amino)butanamide
  • Example 445 (41 mg, 0.051 mmol) was dissolved in dichloromethane: trifluoroacetic acid (4 mL, 1 : 1) at 25 °C for 1 h. The solvents were evaporated and the mixture was triturated with hexanes to precipitate 38 mg (100%) ofthe title compound.
  • Example 468 (2S,3S)-2-( ⁇ [(3-aminobenzyl)(methyl)amino]carbonyl ⁇ amino)-N- ⁇ (lS,2R)-l-benzyl-2- hydroxy-3 - [( ⁇ 4- [(E)-(hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3- methylpentanamide
  • Example 453 (19 mg, 0.026 mmol) was dissolved in ethyl acetate (1 mL) and treated with 10%) Pd/C (6 mg) at 25 °C for 3.5 h. The catalyst was filtered and the solvents were evaporated. The crade residue was purified using 5% methanol/chloroform to give 17 mg (94%>) ofthe title compound.
  • Example 469 (2S,3R)-N- ⁇ (1S,2R)- 1 -benzyl-2-hydroxy-3-[( ⁇ 4-[(E) ⁇ (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-hydroxy-2-[( ⁇ methyl[(2- methyl- 1 ,3 -thiazol-4-yl)methyl] amino ⁇ carbonyl) amino]butanamide
  • Example 451 (25 mg) was dissolved in dichloromethane (2 mL) was freated with trifluoroacetic acid (2 mL) and stined at 25 °C for 1 h. The solvents were evaporated.
  • Example 470 (2S,3R)-N- ⁇ (1S,2R)- 1 -benzyl-3-[(cyclobutyhnethyl)( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)amino]-2-hydroxypropyl ⁇ -3-hydroxy-2- [( ⁇ methyl[(2-methyl-l,3-thiazol-4-yl)methyl]amino ⁇ carbonyl)amino]butanamide
  • Example 452 was freated in a similar manner as in Example 469 to give the title compound.
  • Example 471 A tert-butyl 2-amino-2-thioxoethylcarbamate Boc-glycine (2.34 g, 0.134 mmol) was dissolved in dichloromethane (130 mL) and treated with Lawesson's reagent (2.9 g, 0.52 equivalents) and the mixture was stined at 25 °C for 16 h. The mixture was filtered and the solvents were evaporated. The residue was purified using dichloromethane: ethyl acetate (1:1) to give 2.56 g (100%>) ofthe thioamide.
  • Example 47 IB tert-butyl ⁇ 4-[(methylamino)methyl]- 1 ,3-thiazol-2-yl ⁇ methylcarbamate
  • Example 471A (0.5 g) was dissolved in isopropanol (10 mL) and treated with dichloroacetone (0.33 g, 1 equivalent) and the mixture was stined at 25 °C for 16 h. The solvents were evaporated, and the crade residue was dissolved in isopropanol (2 mL) and treated with 40% methylamine in water (5 mL, 25 equivalents). The solvents were evaporated, and the residue was partitioned between ethyl acetate and sat ⁇ aHCO . The organic layer was separated, dried over MgSO 4 , filtered, and the solvents were evaporated to give 0.48 g ofthe title compound.
  • Example 47 IC methyl (2S,3S)-2-( ⁇ [[(2- ⁇ [(tert-butoxycarbonyl)amino]methyl ⁇ -1 ,3-thiazol-4- yl)methyl](methyl)amino]carbonyl ⁇ amino)-3-methylpentanoate
  • Example 47 IB (0.48 g) was dissolved in tetrahydrofuran (10 mL) and freated with triethyl amine (0.78 mL, 3 equivalent), DMAP (34 mg, 15mol%) followed by Example 406 (0.7 g, 1.2 equivalent) and the mixture was heated to 66 °C for 16 h.
  • Example 47 IC (0.37 g) was dissolved in tefrahydrofuran: water (4 mL, 3:1) and freated with LiOH (0.11 g, 3 equivalents) and the mixture was stined at 25 °C for 30 min.
  • Example 471E tert-butyl (4- ⁇ (5S,8S,9R)-8-benzyl-9-hydroxy-l l-( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)-2,13-dim 2,4,7, 11 -tefraazatetradec- 1 -yl ⁇ - 1 ,3-thiazol-2-yl)methylcarbamate
  • Example 47 ID 35 mg was dissolved in N,N-dimethylformamide (0.85 mL) and treated with EDAC (25 mg, 1.5 equivalents), HOBT (17 mg, 1.5 equivalents), N- methylmorpholine(10 ⁇ L, 1.1 equivalents) followed by Example 18 (35 mg, 1 equivalent), and the mixture was stined at 25 °C for 16 h.
  • Example 47 IF tert-butyl (4- ⁇ (5S,8S,9R)-8-benzyl-9-hydroxy-l l-( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)-2,13-dimethyl-5-[(lS)-l-methylpropyl]-3,6-dioxo- 2,4,7,1 l-tetraazatefradec-l-yl ⁇ -l,3-thiazol-2-yl)methylcarbamate
  • Example 47 IE was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) and stined at 25 °C for 30 min.
  • Boc-Z-alanine 1.0 g, 5.29 mmol
  • ⁇ , ⁇ -dimethylformamide 5 mL
  • EDAC 1.5 g, 7.82 mmol
  • N-hydroxysuccinimide 0.91 g, 7.91 mmol
  • Aqueous ammonium hydroxide solution (15 mL, 28%>) was added and the mixture was stined for 0.5 hours at room temperature.
  • Example 474B tert-butyl (15)-2-amino-l -methyl-2-thioxoethylcarbamate
  • dichloromethane 25 mL
  • Lawesons Reagent 0.54 g, 1.34 mmol
  • the solvent was evaporated and the residue was purified using dichloromethane - 35%o ethyl acetate in dichloromethane to give the product (0.52 g, 100%) yield).
  • Example 474C ethyl 2- ⁇ (lS)-l-[(tert-butoxycarbonyl)amino]ethyl ⁇ -l,3-thiazole-4-carboxylate
  • DME 7 mL
  • pulverized KHCO 3.55 g, 35.46 mmol
  • ethyl bromopyravate 1.65 mL, 13.15 mmol
  • Example 474D tert-butyl (lS)-l- ⁇ 4- [(methylamino)methyl] - 1 ,3 -tl ⁇ iazol-2-yl ⁇ ethylcarbamate
  • LiBH 4 0.15 g, 6.89 mmol
  • Example 474F methyl (2S,3S)-2-( ⁇ [[(2- ⁇ ( IS)- 1 -[(tert-butoxycarbonyl)amino] ethyl ⁇ - 1 ,3 -thiazol-4- yl)methyl](methyl)amino]carbonyl ⁇ amino)-3-methylpentanoate
  • Example 474D (0.305 g, 1.13 mmol) was dissolved in tefrahydrofuran (6 mL) and freated with Example 406 (0.525 g, 1.69 mmol), triethylamine (0.47 mL, 3.37 mmol), and DMAP (0.020 g, 0.16 mmol), at room temperature and the mixture was stined at 80 °C for 16 hours.
  • Example 474G (2S,3S)-2-( ⁇ [[(2- ⁇ (lS)-l-[(tert-butoxycarbonyl)amino]ethyl ⁇ -l,3-thiazol-4- yl)methyl](methyl)amino]carbonyl ⁇ amino)-3-methylpentanoic acid
  • dioxane 3 mL
  • lithium hydroxide 3.0 mL, 0.5 M
  • Example 474H tert-butyl (lS)-l-(4- ⁇ (5S,8S,9R)-8-benzyl-12-cyclopentyl-9-hydroxy-ll-( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)-2-methyl-5-[(lS)-l-methylpropyl]-3,6-dioxo- 2,4,7, 11 -tefraazadodec- 1 -yl ⁇ - 1 ,3 -thiazol-2-yl)ethylcarbamate
  • Example 474G 35 mg was dissolved in N,N-dimethylformamide (0.85 mL) and treated with EDAC (25 mg, 1.5 equivalents), HOBT (17 mg, 1.5 equivalents), N- methylmorpholine(10 ⁇ L, 1.1 equivalents) followed by Example 27 (35 mg, 1 equivalent), and the mixture was stined at 25 °C for 16 h.
  • Example 4741 (2S,3S)-2-( ⁇ [( ⁇ 2-[(lS)-l -aminoethyl]- 1 ,3-thiazol-4- yl ⁇ methyl)(methyl)amino]carbonyl ⁇ amino)-N- ⁇ (lS,2R)-l-benzyl-3-[(cyclopentylmethyl)( ⁇ 4- [(E)-(hydroxyimino)methyl]phenyl ⁇ sulfonyl)amino]-2-hydroxypropyl ⁇ -3- methylpentanamide
  • Example 474H was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) and stined at 25 °C for 30 min.
  • Example 475 (2S,3S)-2-( ⁇ [( ⁇ 2-[(lR)-l-aminoethyl]-l,3-thiazol-4- yl ⁇ methyl)(methyl)amino]carbonyl ⁇ amino)-N- ⁇ (1 S,2R)- 1 -benzyl-3 -[(cyclopentylmethyl)( ⁇ 4- [(E)-(hydroxyimino)methyl]phenyl ⁇ sulfonyl)amino]-2-hydroxypropyl ⁇ -3- methylpentanamide
  • Example 475 was prepared via coupling and deprotection.
  • Example 476A 1 -[6-(hydroxymethyl)-2-pyridinyl]ethanone The title compound was prepared according to the procedure as described in Katsura, Y. et. al., Journal of Medicinal Chemistry, 37, 57-66 (1994).
  • Example 476B 1 - [6-(chloromethyl)-2-pyridinyl] ethanone
  • N,N-dimethylformamide (2 mL) at 0°C was treated phosphorus oxychloride (0.283 mL, 3.04 mmol).
  • the mixture was stined 3 hours at 0°C, quenched with IM sodium bicarbonate, and extracted with ethyl acetate.
  • the organic layer was evaporated, and the residued was purified using 10% ethyl acetate / hexane to give 86 mg (33.4%) of the title compound.
  • Example 476C l- ⁇ 6-[(methylamino)methyl]-2-pyridinyl ⁇ ethanone
  • Example 476B (86 mg, 0.5 mmol) at 25°C was treated with 2 M methylamine in tetrahydrofuran (2 mL, 4 mmol). The reaction was stined at 25°C for 16 hour, the solvent was concentrated and the residue was purified using 10% methanol/dichloromethane with 0.5%) ammonium hydroxide to give 53 mg (72.6%) ofthe title compound.
  • Example 476D tert-butyl (2S,3S)-2-( ⁇ [[(6-acetyl-2-pyridinyl)methyl](methyl)amino]carbonyl ⁇ amino)-3- methylpentanoate
  • Example 406 107 mg,0.3 mmol in N,N- dimethylformamide (2 mL) at 25 °C was treated with diisopropylethylamine (64 ⁇ L, 0.36mmol) followed by N,N-dimethylaminopyridine (5.2 mg, 0.042 mmol).
  • Example 476E (2S,3S)-2-( ⁇ [[(6-acetyl-2-pyridinyl)methyl](methyl)amino]carbonyl ⁇ amino)-3- methylpentanoic acid
  • Example 476D (97 mg, 0.257 mmol) at 25°C was freated with 80% trifluoroacetic acid in dichloromethane (1.5 mL). The reaction was stined at 25°C for 3 hour, the solvent was concentrated and the residue was dissolved in water (0.5 mL) and purified using 7% methanol/dichloromethane to give 100 mg (89.3%.) ofthe title compound.
  • Example 476F (2S,3S)-2-( ⁇ [[(6-acetyl-2- ⁇ yridinyl)methyl](methyl)amino]carbonyl ⁇ amino)-N- ⁇ (lS,2R)-l- benzyl-3-[(cyclopentylmethyl)( ⁇ 4-[(E)-(hydroxyimino)methyl]phenyl ⁇ sulfonyl)amino]-2- hydroxypropyl ⁇ -3 -methylpentanamide
  • Example 476E 99 mg, 0.31 mmol
  • EDAC 88 mg, 1.5 equivalents
  • HOBT 62 mg, 1.5 equivalents
  • N- methylmorpholine(34 ⁇ L, 1 equivalent) followed by addition of Example 27 (164 mg, 1.2 equivalents).
  • Example 476G (2S,3S)-N- ⁇ (lS,2R)-l-benzyl-3-[(cyclopentylmethyl)( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)amino]-2-hydroxypropyl ⁇ -2-( ⁇ [( ⁇ 6-[N- hydroxyethanimidoyl]-2-pyridinyl ⁇ methyl)(methyl)amino]carbonyl ⁇ amino)-3- methylpentanamide
  • Example 476F (75 mg) was dissolved in methanol (2 mL) and combined with hydroxylamine hydrochloride (14 mg, 2 equivalents). The mixture was stined at 25 °C for 16 h. The solvents were evaporated and the residue was purified using 10% methanol/dichloromethane to give 54 mg (70%») ofthe title compound.
  • Example 477 (2S,3S)-2-( ⁇ [( ⁇ 2-[(lS)-l-(acetylamino)ethyl]-l,3-thiazol-4- yl ⁇ methyl)(methyl)amino]carbonyl ⁇ amino)-N- ⁇ (lS,2R)-l-benzyl-3-[(cyclopentylmethyl)( ⁇ 4- [(E)-(hydroxyimino)methyl]phenyl ⁇ sulfonyl)amino]-2 -hydroxypropyl ⁇ -3- methylpentanamide
  • Example 4741 (0.87 g) was dissolved in dichloromethane (0.2 mL) and treated with triethyl amine (3.2 ⁇ L, 2 equivalents) and acetic anhydride (1.3 ⁇ L, 1.2 equivalents), and the mixture was stined at 25 °C for 3 h.
  • Example 478 tert-butyl (1S)-1 -[( ⁇ (1S,2R)- 1 -benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ amino)carbonyl]-2,2- dimethylpropylcarbamate
  • Method D (L)-Boc-t-leucine (55 mg, 0.024 mmol) was dissolved in tefrahydrofuran (10 mL) and treated with triethyl amine (66 ⁇ L, 2 equivalents), 3-(diethylphosphoryloxy)- 1,2,3- benzotriazin-4(3H)-one (DEPBT) (86 mg, 1.2 equivalents), and Example 18 (0.1 g, 1 equivalent) at 25 °C for 16 h.
  • Example 479A hexahydrofuro[2,3-b]furan-3-yl 4-nifrophenyl carbonate To a solution of (3S,3aR,6aS)- and (3R,3aS,6aR)-3-hydroxy-4H-hexahydrofuro[2,3- b]furan (see compound 15 in: Gosh, A.K.; Kincaid, j. F.; Walters, D. E.; Chen, Y.;
  • Example 479B hexahydrofuro[2,3-b]furan-3-yl (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propylcarbamate Method F
  • Example 479 A (10.6 mg, 0.036 mmoles, 1.5 equivalents) was combined with Example 18 (10 mg, 0.024 mmoles) in tetrahydrofuran (0.5 mL) at 25 °C for 24 h. The solvent was evaporated under vacuum, and the residue was purified using 2% methanol/dichloromethane to give 10.9 mg (80% yield) ofthe title compound.
  • Example 162 (Method B), Example 435 (Method E), or Example 479 (Method F).
  • Example 513A methyl (2S)-2-[(chloroacetyl)amino]-3,3-dimethylbutanoate (L)-methyl t-leucinate hydrochloride (1 g) was dissolved in ethyl acetate (6 mL) and water (4 L) and freated with K 2 CO 3 (1.66 g, 3 equivalents) followed by chloroacetyl chloride (0.53 mL, 1.2 equivalents) at 25 °C for 2 h. The organic layer was separated, washed with 10% citric acid, and the solvents were evaporated. The residue was purified by ethyl acetate: hexanes (1:4) to give 1.22 g (100%) ofthe chloro ester.
  • Example 513B methyl (2S)-2-( ⁇ [(3-fluorobenzyl)amino]acetyl ⁇ amino)-3,3-dimethylbutanoate
  • Example 513A (1.22 g) was dissolved in tetrahydrofuran (5 mL) and treated with 3- fluorobenzyl amine (1.9 mL, 3 equivalents) at 60 °C for 16 h. The solvents were evaporated and the residue partitioned between IN ⁇ aHCO 3 and ethyl acetate. The organic layer was separated and purified using ethyl acetate: hexanes (3:2) to give 1.22 g (71 >) ofthe title compound.
  • Example 513C methyl (2S)-2-( ⁇ [(tert-butoxycarbonyl)(3-fluorobenzyl)amino]acetyl ⁇ amino)-3,3- dimethylbutanoate
  • Example 513B (1.22 g) was dissolved in dioxane (14 mL) and treated with IN NaHCO 3 (9 mL, 2.3 equivalents) followed by Boc 2 O (1.11 g, 1.3 equivalents) at 25 °C for 16 h. The mixture was partitioned between water and ethyl acetate, the organic layer separated, and the solvents were evaporated. The residue was purified using ethyl acetate: hexanes (1 :4) to give 1.55 g (96%) ofthe protected amine.
  • Example 513D 2-( ⁇ [(tert-butoxycarbonyl)(3-fluorobenzyl)amino]acetyl ⁇ amino)-3,3-dimethylbutanoic acid
  • Example 513C (1 g) was dissolved in tetrahydrofuran (6 mL) and treated with LiOH (0.133 g, 1.3 equivalents) in water (3 mL) at 0 °C for 16 h. The solvents were evaporated, and the residue was partitioned between water and ethyl acetate. The aqueous layer was separated, acidified with 10% citric acid to pH 2-3, and extracted with ethyl acetate. The organic layer was separated, and the solvents were evaporated. The residue was purified using 10%) methanol/dichloromethane to give 0.9 g (93%>) ofthe acid as epimers at the alpha center which were not separable.
  • Example 513E tert-butyl 2-( ⁇ (lS)-l-[( ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ amino)carbonyl]-2,2- dimethylpropyl ⁇ amino)-2-oxoethyl(3-fluorobenzyl)carbamate
  • Example 513D (0.125 g) was dissolved in N,N-dimethylformamide (2 mL) and freated with EDAC (82 mg, 1.5 equivalents), HOBT (58 mg, 1.5 equivalents), followed by Example 18 (0.12 g, 0.9 equivalent) at 25 °C for 3 d.
  • Example 514E The mixture was partitioned between IN NaHCO 3 and ethyl acetate. The organic layer was separated, and the solvents were evaporated. The residue was separated using ethyl acetate: hexanes (1:1) to give 0.21 g of Example 514E and 0.36 g of Example 513E.
  • Example 513F (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2-( ⁇ [(3- fluorobenzyl)amino]acetyl ⁇ amino)-3,3-dimethylbutanamide
  • Example 513E (0.105 g) was dissolved in 80%> trifluoroacetic acid (3 mL) at 25 °C for 2 h. The solvents were evaporated, and the residue was purified using 10% methanol/ethyl acetate w/0.5% ⁇ H OH to give 53 mg (58%) ofthe title compound.
  • Example 514 tert-butyl 2-( ⁇ (lR)-l-[( ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ amino)carbonyl]-2,2- dimethylpropyl ⁇ amino)-2-oxoethyl(3 -fluorobenzyl)carbamate
  • Example 514F (2R)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2-( ⁇ [(3- fluorobenzyl)amino] acetyl ⁇ amino)-3 ,3 -dimethylbutanamide
  • Example 514E (0.11 g) was de
  • Example 515 A N-Boc-glycyl-(L)-isoleucine (0.5 g) was dissolved in tetrahydrofuran (25 mL) and freated with Boc 2 O (0.64 g, 1.1 equivalents) and IN ⁇ aOH (2.66 mL, 1 equivalent) at 25 °C for 2 h. The mixture was partitioned between ⁇ aHCO 3 and dichloromethane. The aqueous layer was separated, acidified with 10%» citric acid, and exfracted with dichloromethane. The organic layer was separated, dried with MgSO4, filtered, and the solvents were evaporated to give 0.3 g (39%) ofthe Boc compound.
  • Example 515B tert-butyl 2-( ⁇ (lS,2S)-l-[( ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ amino)carbonyl]-2- methylbutyl ⁇ amino)-2-oxoethylcarbamate
  • Example 515A 34 mg was dissolved in N,N-dimethylformamide (3 mL) and treated with EDAC (25 mg, 1.1 eq), HOBT (18 mg, 1.1 equivalents), and Example 18 (50 mg, 1 equivalent) at 25 °C for 16h.
  • Example 515C (2S,3S)-2-[(aminoacetyl)amino]-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-methylpentanamide
  • Example 515B (0.44 g) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (8 mL) at 25 °C for 2.5 h.
  • Example 515D (2S,3S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -2-( ⁇ [(3 - fluorobenzyl)amino]acetyl ⁇ amino)-3-methylpentanamide
  • Example 515C (12 mg) was dissolved in methanol (1 mL) and benzene (1 mL) and freated with 3-fluorobenzaldehyde (2.2 ⁇ L, 1 equivalent), and this mixture is heated to 50 °C for 1.5 h.
  • Example 517 (2S,3S)-N- ⁇ (1S,2R)- 1 -benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-methyl-2-[( ⁇ [(5-nifro-3- thienyl)methyl] amino ⁇ acetyl)amino]pentanamide
  • Example 515D the title compound was prepared by coupling 2-nifrothiophene-3-carboxaldehyde with Example 515C.
  • Example 518A benzyl (15)-l-[( ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ amino)carbonyl]-4-[((Z)- [(tert-butoxycarbonyl)amino] ⁇ [(Z)-tert-butoxycarbonyl]imino ⁇ methyl)amino]butylcarbamate
  • Z-Arginine(Boc) 2 OH cyclohexylamine salt 22 mg was dissolved in water, acidified with 10%) citric acid and exfracted with ethyl acetate.
  • Example 518B benzyl (lS)-4- ⁇ [amino(imino)methyl]amino ⁇ -l-[( ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ amino)carbonyl]butylcarba mate
  • Example 518A (21 mg) was dissolved in 80%> trifluoroacetic acid (1 mL) at 25 °C for
  • Example 519 (2S)-2-amino-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3,3-dimethylbutanamide
  • Example 478 was freated with trifluoroacetic acid as for Example 518B to give the title compound.
  • Example 18 (78.6 mg) was dissolved in tefrahydrofuran (1 mL) and ⁇ , ⁇ - dimethylformamide (0.1 mL) and freated with the product of Example 17 from Part 1 of Method B, (70.5 mg, 1.2 equivalents) and triethyl amine (78 ⁇ L, 3 equivalents) at 25 °C for 2 h. The solvents were evaporated, and the residue was purified using dichloromethane to give 87 mg (68% ⁇ ) ofthe sulfonamide.
  • Example 520B N- ⁇ (2R,3S)-2-hydroxy-3-[( ⁇ 4-[(hydroxyimino)methyl]phenyl ⁇ sulfonyl)amino]-4- phenylbutyl ⁇ -4-[(E)-(hydroxyimino)methyl]-N-isobutylbenzenesulfonamide
  • Example 520A (87 mg) was dissolved in ethanol (1.2 mL) and treated with hydroxylamine hydrochloride (19 mg, 1.5 equivalents) and triethyl amine (91 ⁇ L, 3.5 equivalents) at 75 °C for 1 h. The solvents were evaporated, and the residue was purified using dichloromethane to give 88 mg (100%>) ofthe title compound.
  • Example 521A tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4- methoxyphenyl)sulfonyl]amino ⁇ propylcarbamate
  • (2R,3S)-3- ⁇ -tert-butoxycarbonylamino-l,2-epoxy-4-phenylbutane 0.2 g, 0.76 mmol
  • 2-propanol 4 mL
  • the isobutylamme 1.5 mL, 20 equivalents
  • Example 52 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide
  • Example 521 A (47 mg, 0.093 mmol) was dissolved in trifluoroacetic acid: dichloromethane (4 mL, 1:1) at 25 °C for 1 h. The solvents were evaporated to give 38 mg (100%) ofthe title compound.
  • Example 524 (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4-methoxyphenyl)sulfonyl]amino ⁇ propyl)- 2- ⁇ 3-[(2-isopropyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl ⁇ -3-methylbutanamide
  • Method C Example 144 (25 mg ) was combined with ⁇ -hydroxysuccinimide (10 mg, 1.1 equivalents) and DCC (18 mg, 1.1 equivalents) in dichloromethane (1 mL) and stined for 1 h at 25° C.
  • Example 587A tert-butyl (2S)-2-(3- ⁇ [2-(hydroxymethyl)-l,3-thiazol-4-yl]methyl ⁇ -2-oxo-l-imidazolidinyl)- 3-methylbutanoate
  • Example 273D (509 mg) was dissolved in ethanol (14 mL) added ⁇ aBH 4 (57.6 mg, 1.1 equivalents). The mixture was stined at 25 °C for 3 h and quenched with sat. NH C1 and the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over MgSO 4 . The solvents were evaporated to give 452 mg (88%o) crade alcohol.
  • Example 587B tert-butyl (2S)-3-methyl-2- ⁇ 3-[(2- ⁇ [(methylsulfonyl)oxy]methyl ⁇ -l,3-thiazol-4-yl)methyl]-2- oxo- 1 -imidazolidinyl ⁇ butanoate
  • Example 587 A (452 mg) was dissolved in dichloromethane (12 mL) added triethylamine (683 ⁇ L, 4 equivalents), cooled to 0 °C and methanesulfonyl chloride (190 ⁇ L, 2 equivalents). After 30 min. the solvents were evaporated. The residue was partitioned between ethyl acetate and 10% citric acid solution. The organic layer was separated and washed with 10% NaHCO 3 , brine, dried over MgSO 4 , filtered, and the solvents were evaporated to give 335 mg (61%>) of the title compound.
  • Example 587C (2S)-2-(3- ⁇ [2-(azidomethyl)-l,3-thiazol-4-yl]methyl ⁇ -2-oxo-l-imidazolidinyl)-3- methylbutanoic acid
  • Example 587B (335 mg) was dissolved in N,N-dimethylformamide (5 mL) and LiN 3 (366 mg, 10 equivalents) and the mixture was heated to 50 °C for 2.5 h. The solvents were evaporated and partitioned between ethyl acetate and brine, and the organic layer was separated, dried over MgSO 4 , filtered, and concentrated to give 292 mg of crade azide. The crude azide was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) and stined at 25 °C for 2 h. The solvents were evaporated to give 244 mg (96%) acid.
  • Example 587D (2S)-2-(3- ⁇ [2-(azidomethyl)-l,3-thiazol-4-yl]methyl ⁇ -2-oxo-l-imidazolidinyl)-N-((lS,2R)-l- benzyl-2-hydroxy-3- ⁇ isobutyl[(4-methoxyphenyl)sulfonyl]amino ⁇ propyl)-3- methylbutanamide
  • Example 587C (244 mg) was dissolved in ⁇ , ⁇ -dimethylformamide (7 mL) and HOBT (146 mg, 1.5 equivalents) , EDAC (168 mg, 1.5 equivalents), triethylamine (0.2 mL, 2 equivalents) followed by Example 521B (352 mg, 1.2 equivalents).
  • Example 587E (2S)-2-(3- ⁇ [2-(aminomethyl)-l,3-thiazol-4-yl]methyl ⁇ -2-oxo-l-imidazolidinyl)-N-((lS,2R)-l- benzyl-2-hydroxy-3- ⁇ isobutyl[(4-methoxyphenyl)sulfonyl]amino ⁇ propyl)-3- methylbutanamide
  • Example 587D (270 mg, 0.37 mmol) was dissolved in tetrahydrofuran (3 mL) and water (0.7 mL) followed by triphenylphosphine (TPP) (195 mg, 2 equivalents). The mixture was heated to 50 °C for 1 h.
  • Example 588 (2S)-2-[3-( ⁇ 2-[(acetylamino)methyl]-l,3-thiazol-4-yl ⁇ methyl)-2-oxo-l-imidazolidinyl]-N- ((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4-methoxyphenyl)sulfonyl]amino ⁇ propyl)-3- methylbutanamide
  • Example 587E (11 mg, 0.016 mmol) was dissolved in dichloromethane (0.15 mL) and treated with acetic anhydride (2.2 ⁇ L, 1.5 equivalents) and triethylamine (6.6 ⁇ L, 3 equivalents) at 25 °C for 1 h.
  • Example 592 (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4-methoxyphenyl)sulfonyl]amino ⁇ propyl)- 2-[3-( ⁇ 2-[(hydroxyimino)methyl]-l,3-thiazol-4-yl ⁇ methyl)-2-oxo-l-imidazolidinyl]-3- methylbutanamide
  • Example 587E (10.2 mg, 0.0145 mmol) was dissolved in dichloromethane (0.2 mL) at 0 °C was treated with m-chloroperbenzoic acid (7 mg, 2 equivalents) and the mixture was stined for 2 h.
  • Example 593 methyl (4- ⁇ [3-((lS)-l- ⁇ [((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4- methoxyphenyl)sulfonyl]amino ⁇ propyl)amino]carbonyl ⁇ -2-methylpropyl)-2-oxo- 1 - imidazolidinyl]methyl ⁇ -l,3-thiazol-2-yl)methylcarbamate
  • Example 587E (16.7 mg, 0.023 mmol) was dissolved in dichloromethane (0.4 mL) was treated with triethylamine (6.6 ⁇ L, 2 equivalents) and methyl chloroformate (2 ⁇ L, 1.1 equivalents) at 0 °C for 30 min.
  • Example 594A tert-butyl (2S)-3-methyl-2-[3-( ⁇ 2-[(methylsulfanyl)methyl]-l,3-thiazol-4-yl ⁇ methyl)-2-oxo- 1 -imidazolidinyl]butanoate
  • Example 587B (28 mg, 0.062 mmol) was dissolved in N,N-dimethylfora ⁇ amide (0.6 mL) and treated with sodium methylthiolate (4.8 mg, 1.1 equivalents) at 25 °C for 16 h. The mixture was partitioned between saturated NH 4 C1 and ethyl acetate. The organic layer was separated and dried over MgSO 4 , filtered, and the solvents were evaporated. The residue was purified using ethyl acetate: dichloromethane (1:1) to give 17.4 mg (70%) ofthe title compound.
  • Example 594B (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4-methoxyphenyl)sulfonyl]amino ⁇ propyl)- 3-methyl-2-[3-( ⁇ 2-[(methylsulfanyl)methyl]-l,3-thiazol-4-yl ⁇ methyl)-2-oxo-l- imidazolidinyl]butanamide
  • Example 594A (57 mg, 0.142 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) and stined at 25 °C for 1 h. The solvents were evaporated and the crude acid used directly for the next step.
  • the acid was dissolved in ⁇ , ⁇ -dimethylformamide (1 mL) and treated with EDAC (33 mg, 1.5 equivalents), HOBT (29 mg, 1.5 equivalents), N- methylmorpholine (0.16 mL, 1 equivalent) followed by the Example 18 (58 mg, 1 equivalent) and the mixture was stined at 25 °C for 16 h.
  • the solvents were evaporated and the residue was purified using dichloromethane: ethyl acetate (1:1) to give 12 mg (11%) ofthe title compound.
  • Example 594C (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4-methoxyphenyl)sulfonyl]amino ⁇ propyl)- 3-methyl-2-[3-( ⁇ 2-[(methylsulfonyl)methyl]-l,3-thiazol-4-yl ⁇ methyl)-2-oxo-l- imidazolidinyljbutanamide
  • Example 594B (13 mg, 0.017 mmol) was dissolved in dichloromethane (0.4 mL) and treated with m-chloroperbenzoic acid (8.7 mg, 2 equivalents) at 25 °C for 30 min.
  • Example 595 (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4-methoxyphenyl)sulfonyl]amino ⁇ propyl)- 2-[3-( ⁇ 2-[(diethylamino)methyl]-l,3-thiazol-4-yl ⁇ methyl)-2-oxo-l-imidazolidinyl]-3- methylbutanamide
  • Example 587E was treated in a similar manner as for Example 590 using acetaldehyde instead of formaldehyde was to prepare the title compound.
  • Example 596 (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4-methoxyphenyl)sulfonyl]amino ⁇ propyl)- 2- ⁇ 3-[2-(isopropylamino)-2-oxoethyl]-2-oxo-l-imidazolidinyl ⁇ -3-methylbutanamide
  • Example 620B (5.8 mg, 0.008 mmol) was dissolved in ethanol (0.3 mL) and treated with NaBH (5 mg) and the mixture was stined at 25 °C for 16 h. The solvents were evaporated and the residue was directly used for the next step.
  • the imidazolone was dissolved in HO Ac (1 mL) and treated with Pd(OH) 2 and a hydrogen balloon. The mixture was stined for 16 h, filtered, and the solvents were evaporated. The residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%>) to give 2.7 mg (46%. from imide) ofthe title compound.
  • Example 597 A tert-butyl (2S)-3-methyl-2-[3-( ⁇ 2-[(methylamino)methyl]-l,3-thiazol-4-yl ⁇ methyl)-2-oxo-l- imidazolidinyl]butanoate
  • Example 273D 200 mg, 0.54 mmol was dissolved in toluene: ethanol (2.2 mL, 1:1) was added 2M methylamine in tetrahydrofuran (0.54 mL, 2 equivalents) was heated to 70 °C for 2 h. The mixture was cooled to 25 °C and NaBH 4 (20 mg, 3 equivalents) was added and the mixture was stined at 25 °C for 16 h.
  • Example 597B tert-butyl (2S)-2- ⁇ 3-[(2- ⁇ [[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]methyl ⁇ -l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl ⁇ -3-methylbutanoate
  • Example 597 A (118 mg, 0.3 mmol) was dissolved in dichloromethane (3 mL) a 0 °C and triethylamine (90 ⁇ L, 2.2 equivalents) followed by FMOC-C1 (86 mg, 1.1 equivalents). The mixture was stined at 25 °C for 16 h. The solvents were evaporated and the residue was purified using ethyl acetate: hexanes (1:1) to give 138 mg (76%>) of protected amine.
  • Example 597C 9H-fluoren-9-ylmethyl (4- ⁇ [3-((lS)-l- ⁇ [((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4- methoxyphenyl)sulfonyl] amino ⁇ propy l)amino] carbonyl ⁇ -2-methylpropyl)-2-oxo- 1 - imidazolidinyl]methyl ⁇ - 1 ,3 -thiazol-2-yl)methyl(methyl)carbamate
  • Example 597B 60 mg, 0.099 mmol was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) and stined at 25 °C for 1 h.
  • the solvents were evaporated and the acid was used directly for the next step.
  • the crade acid was dissolved in N,N- dimethylformamide (1 mL) with HOBT (20 mg, 1.5 equivalents) EDAC (29 mg, 1.5 equivalents), and N-methylmorpholine (27 ⁇ L, 2.5 equivalents) followed by the Example 18 (40 mg, 1 equivalent).
  • the mixture was stined at 25 °C for 16 h and the solvents were evaporated.
  • the residue was purified using HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 40 mg (42%) ofthe title compound.
  • Example 599A 9H-fluoren-9-ylmethyl (4- ⁇ [3-((lS,2S)-l- ⁇ [((lS,2R)-l-benzyl-3- ⁇ (cyclopentylmethyl)[(4- methoxyphenyl)sulfonyl]amino ⁇ -2-hydroxypropyl)amino]carbonyl ⁇ -2-methylbutyl)-2-oxo-l- imidazolidinyl]methyl ⁇ - 1 ,3-thiazol-2-yl)methylcarbamate
  • Example 279F (15 mg, 0.027 mmol) was dissolved in N,N-dimethylformamide (0.3 mL) and treated with Example 522 (18 mg, 1.5 equivalents), EDAC (8 mg, 1.5 equivalents), HOBT (6 mg, 1.5 equivalents), and N-methylmorpholine (7 ⁇ L, 2.5 equivalents) at 25 °C for 16 h.
  • Example 599B (2S,3S)-2-(3- ⁇ [2-(aminomethyl)-l,3-thiazol-4-yl]methyl ⁇ -2-oxo-l-imidazolidinyl)-N- ((lS,2R)-l-benzyl-3- ⁇ (cyclopentylmethyl)[(4-methoxyphenyl)sulfonyl]amino ⁇ -2- hydroxypropyl)-3-methylpentanamide
  • Example 599A (12 mg, 0.012 mmol) was dissolved in acetonitrile (0.2 mL) and treated with diethylamine (3 ⁇ L, 3 equivalents) at 25 °C for 2 h.
  • Example 600 (2S,3S)-2-(3- ⁇ 3-[amino(hydroxyimino)methyl]benzyl ⁇ -2-oxo-l-imidazolidinyl)-N-((lS,2R)- 1 -benzyl-2-hydroxy-3- ⁇ isobutyl[(4-methoxyphenyl)sulfonyl]amino ⁇ propyl)-3- methylpentanamide
  • Example 570 (80 mg, 0.11 mmol) was dissolved in ethanol (1 mL) and treated with hydroxylamine hydrochloride (32 mg, 4 equivalents) and triethylamine (0.16 mL, 10 equivalents) at 50 °C for 9 h.
  • Example 601 A benzyl (lS)-l- ⁇ [((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4- methoxyphenyl)sulfonyl]amino ⁇ propyl)amino]carbonyl ⁇ -3-hydroxypropylcarbamate
  • Example 521B (167 mg, 0.41 mmol) was dissolved in pyridine (0.4 mL) and treated with Z-aminobutyrolactone (193 mg, 2 equivalents) (CAS#35677-89-5) and heated to 100 °C for 2 d. The solvents were evaporated and the residue was purified using ethyl acetate to give 235 mg (66%) ofthe title compound.
  • Example 60 IB (26)-2-amino-N-((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4- methoxyphenyl)sulfonyl]amino ⁇ propyl)-4-hydroxybutanamide
  • Example 601 A (73 mg, 0.11 mmol) was dissolved in methanol (2 L) and treated with Pd(OH) 2 /C and stined with a hydrogen balloon at 25 °C for 3 h. The mixture was filtered, rinsed with methanol, and the solvents were evaporated. The amine was used directly without purification.
  • Example 60 IC 9H-fluoren-9-ylmethyl 2-[((lS)-l- ⁇ [((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4- methoxyphenyl)sulfonyl]amino ⁇ propyl)amino]carbonyl ⁇ -3-hydroxypropyl)amino]ethyl[(l- methyl- lH-benzimidazol-2-yl)methyl]carbamate
  • Example 601B (58 mg, 0.11 mmol) and Example 148C (49 mg, 1 equivalent) were dissolved in methanol (0.5 mL) and HO Ac (5 ⁇ L) and treated with ⁇ aC ⁇ BH 3 (15.4 mg, 2 equivalents) at 25 °C for 2 h.
  • Example 60 ID (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4-methoxypl ⁇ enyl)sulfonyl]amino ⁇ propyl)- 4-hydroxy-2- ⁇ 3-[(l -methyl- lH-benzimidazol-2-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide
  • Example 601C (81 mg, 0.088 mmol) was dissolved in ⁇ , ⁇ -dimethylformamide (0.9 mL) and treated with diethylamine (90 ⁇ L) at 25 °C for 1 h.
  • Example 602 (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4-methoxyphenyl)sulfonyl]amino ⁇ propyl)- 3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl ⁇ butanamide
  • Method C Example 292 (50 mg ) was combined with ⁇ -hydroxysuccinimide (28 mg, 1.1 equivalents) and DCC (49 mg, 1.1 equivalents) in dichloromethane (1 mL) and stined for 1 h at 25° C.
  • Example 52 IB 72 mg, 1 equivalent.
  • the mixture was stined for 16 h, evaporated, and was purified using 1% methanol/chloroform to give 74 mg (65%) ofthe title compound.
  • Example 620A [3-((lS)-l- ⁇ [((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4- methoxyphenyl)sulfonyl]amino ⁇ propyl)amino]carbonyl ⁇ -2-methylpropyl)-2,5-dioxo-l- imidazolidinyl] acetic acid
  • Example 607 (161 mg, 0.24 mmol) was dissolved in tetrahydrofuran: water (0.9 mL, 3 : 1) and treated with LiOH (11 mg, 1.1 equivalents) at 25 °C for 2 h.
  • Example 625A N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-(benzyloxy)-N-isobutylbenzenesulfonamide
  • Example 1 (0.13 g, 0.39 mmol) was dissolved in dichloromethane (4 mL) and treated with triethylamine (0.12 mL, 2.2 equivalents) and j-benzyloxybenzenesulfonyl chloride (0.12 g, 1.1 equivalents) at 25 °C for 18 h.
  • the crade mixture was purified using chloroform to give 0.22 g (97%) ofthe title compound.
  • Example 625B N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-hydroxy-N-isobutylbenzenesulfonamide
  • Example 625 A (0.22 g, 0.38 mmol) was dissolved in ethyl acetate (4 mL) and treated with Pd(OH) 2 /C (0.1 g) and a hydrogen balloon at 25 °C for 2 h. The crude mixture was filtered, and the solvents were evaporated to give 0.2 g crude solid. This material was dissolved in dichloromethane: trifluoroacetic acid (6 mL, 1:1) at 25 °C for 1 h.
  • Example 626A tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(4- nitrophenyl)sulfonyl]amino ⁇ propylcarbamate
  • Example 1 (0.64 g, 1.9 mmol) was dissolved in dichloromethane (20 mL) and treated with triethylamine (0.8 mL, 3 equivalents) and ⁇ -nitrobenzenesulfonyl chloride (0.46g, 1.1 equivalents) at 25 °C and stined for 4 h. The reaction mixture was evaporated and purified using 7% ethyl acetate/dichloromethane to give 0.88 g (89%) ofthe title compound.
  • Example 626B 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide
  • Example 626A (0.88g, 1.7 mmol) was dissolved in ethyl acetate (17 mL) and treated with 20% Pd(OH) 2 /C (230 mg, 0.2 equivalent) and a hydrogen balloon at 25 °C for 1 h. The crude mixture was filtered and the solvents were removed by evaporation. This material was dissolved in dichloromethane: trifluoroacetic acid (10 mL, 1:1) at 25 °C for 1 h. The solvents were evaporated, the crade residue was azeotroped twice with ethyl acetate to give 0.75 g (100%) of crade product as the trifluoroacetic acid salt.
  • Example 627 3-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-chloro-N- isobutylbenzenesulfonamide
  • Example 627A tert-butyl (lS,2R)-l-benzyl-3-[[(4-chloro-3-nitrophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropylcarbamate
  • Example 1 (0.64 g, 1.9 mmol) was dissolved in dichloromethane (20 mL) and treated with triethylamine (0.8 mL, 3 equivalents) and ⁇ -chloro-o-nitrobenzenesulfonyl chloride (0.54g, 1.1 equivalent) at 25 °C and stined for 4 h. The reaction mixture was evaporated and purified using 5% ethyl acetate/dichloromethane to give 0.88
  • Example 627B 3-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-chloro-N- isobutylbenzenesulfonamide
  • Example 627A (0.85g, 1.53 mmol) was dissolved in ethanol: acetic acid (20 mL 1:1) and treated with iron (330 mg, 4 equivalents). The reaction was heated to 70 °C for 1 h. The reaction was evaporated and extracted twice with ethyl acetate. The organic layer was washed twice with saturated NaHCO 3 , dried over MgSO 4 , filtered, and evaporated to give 0.91 g of crude product. This material was treated with dichloromethane: trifluoroacetic acid (20 mL, 1:1) at 25 °C for 1 h. The solvents were evaporated to yield 0.80 g of Example 627B (100%).
  • Example 628A 4-(benzyloxy)-3-nitrobenzenesulfonyl chloride To 10 g (41.5 mmol) of 4-hydroxy-3-nitro-benzenesulfonic acid sodium salt dissolved in ethanol (250 mL) was added benzyl bromide (5.4 mL, 1.1 equivalents), 15%) ⁇ aOH solution (13.2 mL, 1.2 equivalents), and water (40 mL). The mixture was heated to 70 °C for 5 h. Additional benzyl bromide (5.4 mL) and 15% ⁇ aOH solution (13 mL) was added and heating was continued for an additional 18 h. The ethanol was removed by evaporation.
  • reaction was filtered through a pad of Celite, washed with water, and dried in a vacuum oven at 50 °C to give 7 g of material. A portion of this material (1.5g, 4.56 mmol) was combined with phosphorous pentachloride (1.14 g, 1.2 equivalents) and phosphorous oxychloride (1.4 mL, 3.3 equivalents) and heated to 100 °C for 18 h. The reaction mixture was partitioned between chloroform and water. The organic layer was washed with a brine solution, dried over MgSO 4 , filtered, and evaporated to leave 1.4 g of crade title compound which was used in the subsequent step.
  • Example 628B tert-butyl ( 1 S,2R)- 1 -benzyl-3 - [ ⁇ [4-(benzyloxy)-3 -nitrophenyl] sulfonyl ⁇ (isobutyl)amino] -2- hydroxypropylcarbamate
  • Example 1 (1.5 g, 4.4 mmol) was dissolved in 25 mL of dichloromethane and treated with Example 628A (1.4 g, 4.2 mmol) and triethylamine (1.3 mL, 2.2 equivalents). The reaction was stined at 25°C for 3 h. The crude mixture was purified using chloroform to give 1.83 mg (74%>) ofthe title compound.
  • Example 628C 3-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-hy ⁇ LxOxy-N- isobutylbenzenesulfonamide
  • Example 628B (450mg, 0.72 mmol) was dissolved in ethyl acetate (60 mL) and treated with 20% Pd(OH) 2 /C (200 mg, 0.1 equivalent ) and a hydrogen filled balloon at 25 °C for 3 h. The reaction was filtered and evaporated to leave 376 mg of crade material. This was dissolved in dichloromethane: trifluoroacetic acid (6 mL, 1:1) and stined at 25 °C for 1.5 h.
  • Example 629A (lR,2S)-l- ⁇ [ ⁇ [4-(benzyloxy)-3-nitrophenyl]sulfonyl ⁇ (isobutyl)amino]methyl ⁇ -2-[(tert- butoxycarbonyl)amino]-3-phenylpropyl acetate
  • Example 628B (1.83 g, 2.9 mmol) was dissolved in dichloromethane (30 mL) and treated with triethylamine (0.6 mL, 1.5 equivalents), acetic anhydride (0.3 mmol, 1.1 equivalents), and a catalytic amount of 4-(dimethylamino)pyridine. The reaction was stined at 25 °C for 18h and purifie using ethyl acetate/hexane to yield 1.82 g (93%>) ofthe title compound.
  • Example 629B (lR,2S)-l- ⁇ [ ⁇ [3-amino-4-(benzyloxy)phenyl]sulfonyl ⁇ (isobutyl)amino]methyl ⁇ -2-[(tert- butoxycarbonyl)amino]-3-phenylpropyl acetate
  • Example 629A (1.8 g, 2.7 mmol) was dissolved ethanol (25 mL) and acetic acid (5 mL). The solution was treated with iron powder (600 mg, 4equivalents) and heated to 50 °C for 1.5 h. The solvents were removed by evaporation.
  • Example 629C (lR,2S)-l- ⁇ [[(4-(benzyloxy)-3- ⁇ [(l-methyl-lH-imidazol-4- yl)sulfonyl]amino ⁇ phenyl)sulfonyl](isobutyl)amino]methyl ⁇ -2-[(tert- butoxycarbonyl)amino]-3-phenylpropyl acetate
  • Example 629B 75 mg, 0.12 mmol was dissolved in 1 mL of dichloromethane and treated with triethylamine (0.049 mL, 3 equivalents), l-methylimidazole-4-sulfonyl chloride (32 mg, 1.5 equivalents), and a catalytic amount of 4-(dimethylamino)pyridine. The reaction was stined at 40°C for 4 h. The reaction was purified using 2%>methanol/CHCl 3 to give 36 mg (39%o) ofthe title compound.
  • Example 629D tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- ⁇ [(l-methyl-lH-imidazol-4- yl)sulfonyl]amino ⁇ phenyl)sulfonyl](isobutyl)amino]propylcarbamate
  • Example 629C (24 mg, 0.031 mmol) was dissolved in 1 mL of methanol and treated with 20%) Pd(OH) 2 /C (20 mg) and stined at 25 °C under a hydrogen balloon atmosphere for 1 h. The reaction was filtered and evaporated to give 19 mg of crude product.
  • Example 629E N-(5- ⁇ [[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl ⁇ -2- hydroxyphenyl)- 1 -methyl- lZ -imidazole-4-sulfonamide
  • Example 629D (5 mg, 0.008 mmol) was dissolved in dichloromethane: trifluoroacetic acid (0.5 mL, 2:1) and stined at 25 °C for 1 h. The reaction was evaporated and azeotroped with toluene (3x) to give the title compound.
  • Example 630A 3-pyridinesulfonyl chloride A mixture of 3-pyridinesulfonic acid (1.0 g, 6.3 mmol), phosphorous pentachloride
  • Example 63 OB (lR,2S)-l- ⁇ [( ⁇ 4-(benzyloxy)-3-[(3- pyridinylsulfonyl)amino]phenyl ⁇ sulfonyl)(isobutyl)amino]methyl ⁇ -2-[(tert- butoxycarbonyl)amino]-3-phenylpropyl acetate
  • Example 629B 75 mg, 0.12 mmol
  • Example 630A Example 630A (43 mg, 1.7 equivalents) at 25 °C and stined for 72 h.
  • Example 630C tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-hydroxy-3-[(3- pyridinylsulfonyl)amino]phenyl ⁇ sulfonyl)(isobutyl)amino]propylcarbamate
  • Example 630B (67 mg, 0.086 mmol) was dissolved in 1 mL of methanol and treated with K 2 CO 3 (15 mg, 1.2 equivalents) at 25 °C for 18 h.
  • Example 630D N-(5- ⁇ [[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl ⁇ -2- hydroxyphenyl)-3-pyridinesulfonamide
  • Example 630C (22 mg, 0.034 mmol) was dissolved in dichloromethane: trifluoroacetic acid (0.4 mL, 1:1) and stined at 25 °C for 1.5 h. The reaction was evaporated and azeotroped with toluene (3x) to give the title compound.
  • Example 631 A (lR,2S)-l- ⁇ [( ⁇ 4-(benzyloxy)-3- [(methylsulfonyl)amino]phenyl ⁇ sulfonyl)(isobutyl)amino]methyl ⁇ -2-[(tert- butoxycarbonyl)amino]-3-phenylpropyl acetate
  • Example 628B (75 mg, 0.11 mmol) was dissolved in 1.1 mL of dichloromethane, cooled to -78 °C and treated with pyridine (0.027 mL, 3 equivalents), and methanesulfonyl chloride (0.016 mL, 1.8 equivalents). The reaction was allowed to warm to 25 °C and stined for 18 h. The reaction mixture was evaporated and purified using 20%> ethyl acetate/chloroform to give 91 mg ofthe title compound (99%>).
  • Example 63 IB tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-hydroxy-3- [(methylsulfonyl)amino]phenyl ⁇ sulfonyl)(isobutyl)amino]propylcarbamate
  • Example 631A (90 mg, 0.13 mmol) was dissolved in 1.3 mL of methanol, treated with
  • Example 63 IB 35 mg, 0.060 mmol was dissolved in dichloromethane: trifluoroacetic acid (0.3 mL, 1:1) and stined at 25 °C for 1.5 h. The reaction was evaporated and azeotroped with toluene (3x) to give the title compound.
  • Example 633 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3,5-dichloro-2-hydroxy-N- isobutylbenzenesulfonamide 3,5-dichloro-6-hydroxy benzenesulphonyl chloride (97 mg, 0.372 mmol) was dissolved in 1 mL of dichloromethane and treated with NO-bis(trimethylsilyl)acetamide (0.092 mL, 1 equivalent) and stined at 25 °C for 5 h. The reaction mixture was treated with Example 1 (100 mg, 0.8 equivalents) and triethylamine (0.109 mL, 2.1 equivalents) and stined an additional hour.
  • the reaction was diluted with dichloromethane, washed with water, dried over MgSO 4 , and evaporated to give 240 mg of a foamy solid.
  • This material was stined with dichloromethane: trifluoroacetic acid (4.5 mL, 2:1) for 1.5 h.
  • the reaction was evaporated, redissolved in 10%)inethanol/dichloromethane, washed with saturated ⁇ aHCO 3 solution, and purified using 10%methanol/dichloromethane to give 79 mg ofthe title compound (57%>).
  • Example 634A 4-(benzyloxy)-3-methylbenzenesulfonyl chloride
  • O-Cresol-4-sulfonic acid (6 g, 31.88 mmol) was stined with benzyl bromide (9.5 mL, 2.5 equivalent), 15%> aqueous ⁇ aOH (34 mL, 4 equivalents), and ethanol (150 mL) at 67 °C for 22h.
  • the solvent was evaporated and the reaction was slurried with 10 mL of water, filtered, and the resulting white solid was washed with water twice.
  • the material was dried in vacuo to give 8.2 g ofthe O-benzylated sodium salt.
  • Example 634B tert-butyl (lS,2R)-l-benzyl-3-[ ⁇ [4-(benzyloxy)-3-methylphenyl]sulfonyl ⁇ (isobutyl)amino]-2- hydroxypropylcarbamate
  • Example 1 100 mg, 0.30 mmol dissolved in 2 mL of dichloromethane was combined with Example 634A (lmg, 1.2 equivalents) and triethylamine (.0125 mL, 3 equivalents) and stined for 4 h. The reaction was purified using l%methanol/dichloromethane to give 200 mg (100%)) of crade title compound.
  • Example 634C N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-hydroxy-N-isobutyl-3- methylbenzenesulfonamide
  • Example 634B (200 mg crade, 0.3 mmol) was dissolved in 2 mL of ethanol and treated with 10% Pd/C (100 mg). The reaction was stined under hydrogen balloon pressure for 24 h. The reaction was filtered, evaporated, and purified using l%>methanol/dichloromethane to give 80 mg ofthe debenzylated product. This material was stined with dichloromethane: trifluoroacetic acid (3 mL, 2:1) for 2.5 h.
  • Example 635A 5-fluoro-4-hydroxy-2-methylbenzenesulfonyl chloride To a solution of chlorosulfonic acid (1.5 g, 13.3 mmol) dissolved in 10 mL of dichloromethane was added 2-fluoro-5-methylphenol (1.1 g, 8.86 mmol) dropwise. After 10 minutes, the reaction was quenched by adding to ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO 4 , filtered, and concentrated to give 150 mg (7.5%o) ofthe title compound.
  • Example 635B N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-5-fluoro-4-hydroxy-N-isobutyl-2- methylbenzenesulfonamide
  • Example 635A (95 mg, 0.424 mmol) was dissolved in 1 mL of dichloromethane, treated withNO-bis(trimethylsilyl)acetamide (0.105 mL, 1 equivalent), and stined at 25 °C for 5 h. The reaction mixture was treated with Example 1 (100 mg, 0.7 equivalent), triethylamine (0.109 mL, 2.1 equivalents), and stined an additional hour.
  • Example 636A 5-chloro-4-hydroxy-2-methylbenzenesulfonyl chloride To a solution of chlorosulfonic acid (1.22 g, 10.5 mmol) dissolved in 10 mL of dichloromethane was added 2-chloro-5-methylphenol (1.0 g, 7.0 mmol) dropwise. After 10 minutes, the reaction was quenched by pouring it into ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO 4 , filtered, and concentrated to give 120 mg (7.1 %>) of the title compound.
  • Example 636B N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-5-chloro-4-hydroxy-N-isobutyl-2- methylbenzenesulfonamide
  • Example 636A 120 mg, 0.50 mmol was dissolved in 1 mL of dichloromethane, treated with NO-bis(trimethylsilyl)acetamide (0.123 mL, 1 equivalent), and stined at 25 °C for 5 h. The reaction mixture was treated with Example 1 (117 mg, 0.7 equivalent), triethylamine (0.106 mL, 2.1 equivalents), and stined an additional hour.
  • the reaction was diluted with dichloromethane, washed with water, dried over MgSO , filtered, and evaporated to give a foamy solid.
  • This material was stined with dichloromethane: trifluoroacetic acid (4.5 mL, 2:1) for 1.5 h.
  • the reaction was evaporated, redissolved in 10%methanol/dichloromethane, washed with saturated ⁇ aHCO 3 solution, and purified using 10%methanol/dichloromethane to give 33 mg (21%) ofthe title compound.
  • Example 637A 3-chloro-4-hydroxy-5-methylbenzenesulfonyl chloride To a solution of chlorosulfonic acid (1.22 g, 10.5 mmol) dissolved in 10 mL of dichloromethane was added 2-chloro-5-methylphenol (1.0 g, 7.0 mmol) dropwise. After 10 minutes, the reaction was quenched by pouring it into ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO 4 , filtered, and concentrated to give 190 mg (11.3%) ofthe title compound.
  • Example 637B N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-chloro-4-hydroxy-N-isobutyl-5- methylbenzenesulfonamide
  • Example 637A (190 mg, 0.788 mmol) was dissolved in 2 mL of dichloromethane, treated withNO-bis(trimethylsilyl)acetamide (0.194 mL, 1 equivalent), and stined at 25 °C for 5 h.t The reaction mixture was treated with Example 1 (183 mg, 0.7 equivalent), triethylamine (0.230 mL, 2.1 equivalents), and stined an additional hour.
  • the reaction was diluted with dichloromethane, washed with water, dried over MgSO 4; and evaporated to give a foamy solid.
  • This material was stined with dichloromethane: trifluoroacetic acid (4.5 mL, 2:1) for 2 h.
  • the reaction was evaporated, redissolved in 10%methanol/dichloromethane, washed with saturated ⁇ aHCO 3 solution, and purified using 7% methanol/dichloromethane to give 110 mg (46%>) ofthe title compound.
  • Example 638 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-chloro-4-hydroxy-N-isobutyl-5- methylbenzenesulfonamide
  • Example 638 A 2-chloro-4-hydroxy-5-methylbenzenesulfonyl chloride To a solution of chlorosulfonic acid (3.69 g, 31.65 mmol) dissolved in 30 mL of dichloromethane was added 3-chloro-6-methylphenol (3.0 g, 21.1 mmol) dropwise. After 10 minutes, the reaction was quenched by pouring it into ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO 4 , filtered, and concentrated to give 120 mg (2.4%) ofthe title compound.
  • Example 638B N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-chloro-4-hydroxy-N-isobutyl-5- methylbenzenesulfonamide
  • Example 638A 120 mg, 0.497 mmol was dissolved in 2 mL of dichloromethane, treated with NO-bis(trimethylsilyl)acetamide (0.135 mL, 1.1 equivalents), and stined at 25 °C for 5 h. The reaction mixture was treated with Example 1 (132 mg, 0.7 equivalent), triethylamine (0.164 mL, 2.1 equivalents), and stined an additional hour.
  • Example 639 A 4-hydroxy-3 -nitrob enzenesulfonyl chloride To a solution of chlorosulfonic acid (12.0 mL, 180 mmol) at 0 °C was added 2- nitrophenol (8.35g, 60.0 mmol) in small portions over 1 h. The reaction was heated to 60 °C for 20 minutes and allowed to stir for 18 h at 25 C. The reaction was quenched by pouring it into 100 g of ice. The reaction was extracted with chloroform (3x), washed with cold water (2x), dried over MgSO 4 , filtered, and concentrated to give 9.06 g (64%>) ofthe title compound.
  • Example 639B tert-butyl ( 1S,2R)- 1 -benzyl-2-hydroxy-3 - [[(4-hydroxy-3 - nitrophenyl)sulfonyl](isobutyl)amino]propylcarbamate
  • Example 639A (1.06 g, 4.46 mmol) was dissolved in 22 mL of dichloromethane, treated with NO-bis(trimethylsilyl)acetamide (1.1 mL, 1 equivalent), and stined at 25 °C for 3 h.
  • Example 1 (1.5 g, 1 equivalent) in 10 mL of dichloromethane, triethylamine (2.0 mL, 3 equivalents), and stined over 72 h.
  • the reaction was washed with water, dried over MgSO 4 , filtered, and evaporated.
  • This material was dissolved in tetrahydrofuran (20 mL) and treated with tetrabutylammonium fluoride (15.0 mL, 3 equivalents) for 2 h. at 25 °C.
  • Ethyl acetate was added and the reaction was washed with 10%) citric acid, water (2x), and brine.
  • the reaction was dried over MgSO 4 , filtered and concentrated to give 2.1 g (87.5%) ofthe title compound.
  • Example 639C tert-butyl (lS,2R)-l-benzyl-3- ⁇ isobutyl[(3-nitro-4- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ phenyl)sulfonyl]amino ⁇ -2- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ propylcarbamate
  • Example 639B (l.Og, 1.86 mmol) in 10 mL of NN-dimethylformamide was treated with 2-(trimethylsilyl)ethoxymethyl chloride (1.30 mL, 4.0 equivalents) and NN- diisopropylethylamine (2.0 mL, 6 equivalents) at 50 °C for 18 h.
  • Example 639D tert-butyl (lS,2R)-3-[[(3-amino-4- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ phenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ propylcarbamate
  • Example 639C (800 mg, 1.0 mmol) was dissolved in 5 mL of ethyl acetate and treated with 20% Pd(OH) 2 /C (200 mg, 0.28 equivalent) under hydrogen balloon pressure for 3 h. The reaction was filtered, concentrated and purified using 5%> ethyl acetate/chloroform to give 599 mg (78%) ofthe title compound.
  • Example 639E tert-butyl ( 1 S,2R)- 1 -benzyl-3 - ⁇ isobutyl[(3 - ⁇ [(methylamino)sulfonyl] amino ⁇ -4- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ phenyl)sulfonyl] amino ⁇ -2- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ propylcarbamate
  • Example 639D (100 mg, 0.13 mmol) in 1.3 mL of dichloromethane was treated with pyridine (0.025 mL, 2.4 equivalents) and N-methyl sulfamoyl chloride (ref: JOC 1976, 41, 4028)(0.014 mL, 1.2 equivalent) at 25 °C for 18 h. The reaction was concentrated and purified using 10%> ethyl acetate/chloroform to give 106 mg (95%) ofthe title compound
  • Example 639F' N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-hydroxy-N-isobutyl-3- ⁇ [(methylamino)sulfonyl] amino ⁇ benzenesulfonamide
  • Example 639E (25 mg, 0.03 mmol) was dissolved in methanol (0.22 mL) and 4 ⁇ HCI (0.07 mL, 9.3 equivalents). The reaction was stined at 25 °C for 18 h. The reaction was concentrated to give 15 mg (100%) ofthe title compound.
  • Example 640A tert-butyl (lS,2R)-l-benzyl-3-[[(3-[(ethoxycarbonyl)amino]-4- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ phenyl)sulfonyl](isobutyl)amino]-2- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ propylcarbamate
  • Example 639D 50 mg, 0.065 mmol
  • pyridine 0.012 mL, 2.4 equivalents
  • ethyl chloroformate 0.007 mL, 1.2 equivalents
  • Example 640B ethyl 5- ⁇ [[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl ⁇ -2- hydroxyphenylcarbamate
  • Example 640A (57 mg, 0.067 mmol) was dissolved in 0.75 mL of methanol, treated with 4 N HCI (0.25 mL, 15 equivalents) and stined at 25 °C for 2 h. The solvents were evaporated to yield 32 mg ofthe title compound (100%>).
  • Example 641 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-hydroxy-N-isobutyl-3- (methylamino)benzenesulfonamide
  • Example 641A tert-butyl (lS,2R)-l-benzyl-3- ⁇ isobutyl[(3-(methylamino)-4- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ phenyl)sulfonyl]amino ⁇ -2- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ propylcarbamate
  • Example 639D (125 mg, 0.16 mmol) was dissolved in 1.8 mL of acetonitrile and treated with formaldehyde (0.065 mL, 5 equivalents), sodium cyanoborohydride (20 mg, 2 equivalents), and acetic acid (0.018 mL, 2 equivalents).
  • Example 641B N-[(2R,3S)-3-amino-2-hydroxy-4- ⁇ henylbutyl]-4-hydroxy-N-isobutyl-3- (methylamino)benzenesulfonamide
  • Example 641A (36 mg, 0.05 mmol) was dissolved in 0.3 mL of methanol and treated with 4 ⁇ HCI (0.3 mL, 24 equivalents). Stirring was continued at 25 °C for 2 h. The reaction was concentrated to yield 21 mg ofthe title compound (100%)).
  • Example 642A tert-butyl (lS,2R)-l-benzyl-3-[[(3-(dimethylamino)-4- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ phenyl)sulfonyl](isobutyl)amino]-2- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ propylcarbamate
  • Example 639D (125 mg, 0.16 mmol) was dissolved in 1.8 mL of acetonitrile and treated with formaldehyde (0.065 mL, 5 equivalents), sodium cyanoborohydride (20 mg, 2 equivalents), and acetic acid (0.018 mL, 2 equivalents). The reaction was stined for 18 h. at 25 °C. Purification was performed using 10%> ethyl acetate/chloroform to give 54 mg (43%) ofthe title compound.
  • Example 642B N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-(dimethylamino)-4-hydroxy-N- isobutylbenzenesulfonamide
  • Example 642A 54 mg, 0.07 mmol was dissolved in 0.4 mL of methanol and treated with 4 ⁇ HCI (0.4 mL, 23 equivalents). Stirring was continued at 25 °C for 2 h. The reaction was concentrated to yield 30 mg ofthe title compound (100%o).
  • Example 643 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3- ⁇ [(ethylamino)carbonyl]amino ⁇ -4-hydroxy- N-isobutylbenzenesulfonamide
  • Example 643A tert-butyl (lS,2R)-l-benzyl-3-[[(3- ⁇ [(ethylamino)carbonyl]amino ⁇ -4- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ phenyl)sulfonyl](isobutyl)amino]-2- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ propylcarbamate
  • Example 639D 50 mg, 0.065 mmol was dissolved in 0.2 mL of toluene and treated with ethyl isocyanate (0.1 mL, 20 equivalents). The reaction was stined at 50 °C for 18
  • Example 643B N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3- ⁇ [(ethylamino)carbonyl]amino ⁇ -4-hydroxy- N-isobutylbenzenesulfonamide
  • Example 643A (35 mg, 0.042 mmol) was dissolved in 0.25 mL of methanol and treated with 4 N HCI (0.25 mL, 24 equivalents). Stirring was continued at 25 °C for 2 h. The reaction was concentrated to yield 30 mg ofthe title compound (100%).
  • Example 644 methyl 5- ⁇ [[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl ⁇ -2- hydroxyphenylcarbamate
  • Example 639D (57 mg, 0.074 mmol) was dissolved in 0.8 mL of dichloromethane and treated with pyridine (0.014 mL, 2.4 equivalents) and methyl chloroformate (0.007 mL, 1.2 equivalents). The reaction was stined at 25 °C for 18 h. Purification was performed using 10% ethyl acetate/chloroform to give 58.0 (95%>) ofthe title compoimd.
  • Example 644B methyl 5- ⁇ [[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl ⁇ -2- hydroxyphenylcarbamate
  • Example 644A (56 mg, 0.068 mmol) was dissolved in 0.3 mL of methanol and treated with 4 N HCI (0.3 mL, 18 equivalents) and stined at 25 °C for 2 h. The reaction was concentrated to yield 31 mg ofthe title compound (100%>).
  • Example 645A benzyl 5- ⁇ [((2R,3S)-3-[(tert-butoxycarbonyl)amino]-4-phenyl-2- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ butyl)(isobutyl)amino] sulfonyl ⁇ -2- ⁇ [2- (trimethylsilyl)ethoxy]methoxy ⁇ phenylcarbamate
  • Example 639D (57 mg, 0.074 mmol) was dissolved in 0.8 mL of dichloromethane and treated with pyridine (0.014 mL, 2.4 equivalents) and benzyl chloroformate (0.013 mL, 1.2 equivalents).
  • Example 645B benzyl 5- ⁇ [[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl ⁇ -2- hydroxyphenylcarbamate
  • Example 645A (49 mg, 0.056 mmol) was dissolved in 0.3 mL of methanol and treated with 4 N HCI (0.3 mL, 21 equivalents). Stirring was continued at 25 °C for 2 h. The reaction was concentrated to yield 30 mg (100%) ofthe title compound.
  • Example 646A 2-oxo-2,3-dihydro-l,3-benzoxazole-6-sulfonyl chloride
  • Benzoxazolinone (13.5 g, 0.1 mol) was added slowly to a 0 °C solution of chlorosulfonic acid (33.29 mL, 5 equivalents).
  • the reaction was warmed to 25 °C and stined for 0.5 h, heated to 60°C for 3 h.
  • the reaction was cooled to 25 °C, poured into ice, filtered, and rinsed with water.
  • Example 646B tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(2-oxo-2,3-dihydro-l,3-benzoxazol-6- yl)sulfonyl]amino ⁇ propylcarbamate
  • Example 1 200 mg, 0.6 mmol
  • Example 646A 175 mg, 1.25 equivalents
  • triethylamine (0.21 mL, 2.5 equivalents).
  • the reaction was purified using 2%methanol/dichloromethane to give 370 mg (58%>) ofthe title compound.
  • Example 646C 4-amino-N-[(2R,3iS)-3-amino-2-hydroxy-4-phenylbutyl]-3-hydroxy-N- isobutylbenzenesulfonamide
  • Example 1 (2.27 g, 6.8 mmol) in 20 mL of dichloromethane at 25 °C was treated with triethylamine (3.75 mL, 4 equivalents) followed by dropwise addition of 4-vinylbenzene sulfonyl chloride (1.6 g, 1.2 equivalents). Stirring was continued for 16 h. after which the reaction was quenched with 1 ⁇ ⁇ aHCO 3 , and evaporated. The material was purified using 20%) ethyl acetate/hexane to give 1.5 g (44%) ofthe title compound.
  • Example 647B tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-[ ⁇ [4-(2- hydroxyethyl)phenyl]sulfonyl ⁇ (isobutyl)amino]propylcarbamate
  • Example 647A (100 mg, 0.2 mmol) was dissolved in 3 mL of tetrahydrofuran at 0 °C and treated with borane-methyl sulfide complex (2 M/tetrahydrofuran, 0.3 mL, 3 equivalents). Stirring was continued for 3 h after which water (0.8 mL), followed by an aqueous solution of 1 N NaOH (0.3 ml) was added.
  • Example 647C N-[(2R,3S)-3-amino-2-hydroxy-4- ⁇ henylbutyl]-4-(2-hydroxyethyl)-N- isobutylbenzenesulfonamide
  • Example 647B (37 mg, 0.0712 mmol) was dissolved in 0.2 mL of dichloromethane and treated with 0.8 mL of trifluoroacetic acid and stined at 25 °C for 3 h. The reaction was evaporated and purified using 5% ⁇ methanol/dichloromethane (w/ 0.5%o ⁇ H 4 OH) to give 16 mg (53.5%o) ofthe title compound.
  • Example 1 400 mg, 1.2 mmol was dissolved in 8 mL of dichloromethane and treated with / p-nitro benzenesulfonyl chloride (0.316 g, 1.2 equivalents) and triethylamine (0.414 mL, 2.5 equivalents). The reaction was stined at 25 °C for 16 h, and purified using 2% methanol/dichloromethane to give 0.56 g (90%>) ofthe title compound.
  • Example 648B tert-butyl (lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropylcarbamate
  • Example 648A (0.56 g, 1.07 mmol) in 10 mL of ethyl acetate was treated with 20%
  • Example 648C N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4- [(methylsulfonyl)amino]benzenesulfonamide
  • Example 648B (150 mg, 0.3 mmol) in 0.5 mL of dichloromethane was treated with pyridine (0.5 mL, 20 equivalents) and methanesulfonyl chloride (0.06 mL, 2.2 equivalents) at 25 °C for 5 h.
  • the reaction was quenched with 1 ⁇ ⁇ aHCO 3 , diluted with dichloromethane, concentrated, and purified using 1%> methanol/20%> ethyl acetate/dichloromethane to give 150 mg (87%) of product.
  • This material was dissolved in 0.2 mL of dichloromethane and treated with 0.5 mL of trifluoroacetic acid at 25 °C for 3 h.
  • the reaction was quenched with 10 mL of water, made alkaline with 1 N NaHCO and extracted with ethyl acetate. This material was purified using 5%> methanol/dichloromethane (w/ 1% NH 4 OH) to give 109 mg (88%) of the title compound.
  • Example 649 (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl] (isobutyl)amino]propyl ⁇ -3 -methyl-2- ⁇ 3 -[(2-methyl- 1 ,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl ⁇ butanamide
  • Example 143 (59 mg, 0.198 mmol) was combined with N-hydroxysuccinimide (25 mg, 1.1 equivalents) and DCC (45 mg, 1.1 equivalents) in dichloromethane (1 mL) and stined for 1 h at 25° C.
  • Example 711 (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 4-[(E)- (hydroxyimino)methyl]phenyl ⁇ sulfonyl)(neopentyl)amino]propyl ⁇ -3-methyl-2- ⁇ 3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl ⁇ butanamide
  • Example 143D 64 mg, 0.21 mmol
  • EDAC 66.3 mg, 2 equivalents
  • HOBT 58 mg, 2 equivalents
  • Example 26 (111 mg, 1.2 equivalents), and N-methylmorpholine (47 ⁇ L, 2 equivalents) at 25 °C for 16 h.
  • Example 712 A (2S)-N- ⁇ (lS,2R)-3-[ ⁇ [4-((E)- ⁇ [(3- aminopropanoyl)oxy]imino ⁇ methyl)phenyl]sulfonyl ⁇ (isobutyl)amino]-l-benzyl-2- hydroxy ⁇ ropyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl ⁇ butanamide
  • Example 270 (127 mg, 0.18 mmol ) was dissolved in dichloromethane (1.8 mL) and treated with Boc- ⁇ -alanine hydroxysuccinimide ester (75 mg, 1.4 equivalents), N- methylmorpholine (40 ⁇ L, 2 equivalents) and DMAP (30 mg, 1.4 equivalents) at 25 °C for 18 h.
  • Example 712B (2S)-N- ⁇ (lS,2R)-3-[ ⁇ [4-((E)- ⁇ [(3- aminopropanoyl)oxy]imino ⁇ methyl)phenyl]sulfonyl ⁇ (isobutyl)amino]-l-benzyl-2- hydroxypropyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide
  • Example 712 A 150 mg, 0.17 mmol was dissolved in dichloromethane : trifluoroacetic acid (3 mL, 2:1) at 25 °C for 30 min.
  • Example 713 (2S)-N-[(lS,2R)-l-benzyl-2-hydroxy-3-(isobutylamino)propyl]-3-methyl-2- ⁇ 3-[(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl ⁇ butanamide
  • Example 713 A (2R,3iS)-3-amino-l-(isobutylamino)-4-phenyl-2-butanol
  • Example 1 (3 g, 8.9 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (8 mL, 12 equivalents) and stined for 5 h at 25 °C.
  • the mixture was quenched with water (50 mL), the aqueous layer was made alkaline to pH 9 with ⁇ aHCO 3 .
  • the mixture was stined for 3 h, and the solids were filtered and dried in vacuo to give 2.5 g (100%>) ofthe diamine.
  • Example 713B (2S)-N-[(lS,2R)-l-benzyl-2-hydroxy-3-(isobutylamino)pro ⁇ yl]-3-methyl-2- ⁇ 3-[(2-methyl- 1,3 -thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl ⁇ butanamide
  • Example 143D (1 g, 3.4 mmol) was combined with the Example 713A (1.5 g, 1.5 equivalents) in ⁇ , ⁇ -dimethylformamide (50 mL) and to this mixture was added HOBT (0.6 g, 1.5 equivalents) and EDAC (0.86 g, 1.5 equivalents).
  • Example 714 (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(3-methoxyphenyl)sulfonyl]amino ⁇ propyl)- 3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl ⁇ butanamide
  • Example 713B (20 mg, 0.04 mmol) was dissolved in dichloromethane (0.5 mL) and treated with triethylamine (13.7 ⁇ L, 2.5 equivalents) followed by 3-methoxybenzene sulfonyl chloride (9.8 mg, 1.2 equivalents) at 25 °C for 16 h.
  • Example 761 (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[[(3- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo- 1 -imidazolidinyljbutanamide
  • Example 714 (31 mg, 0.045 mmol) in dichloromethane (3 mL) was added BBr (20 ⁇ L, 5 equivalents) and stined for 2 h at 25 °C. The mixture was quenched with IN ⁇ aHCO 3 and extracted with ethyl acetate. The solvents were evaporated and the residue was purified using ethyl acetate to give 21 mg (69%) ofthe title compound.
  • Example 762 (2S)-N- ⁇ (lS,2R)-l-benzyl-3-[[(5-bromo-2-hydroxyphenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl ⁇ butanamide
  • Example 747 was treated with BBr to give the title compound.
  • Example 763 (2S)-N- ⁇ (lS,2R)-l-benzyl-3-[ ⁇ [4-(l,2-dihydroxyethyl)phenyl]sulfonyl ⁇ (isobutyl)amino]-2- hydroxypropyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide
  • Example 749 (30 mg, 0.044 mmol) dissolved in tetrahydrofuran (1 L) and water (0.2 mL) was added 4% weight OsO 4 in water (16.3 ⁇ L, 6 mol%) and ⁇ MMO (5.2 mg, 1.2 equivalents).
  • the mixture was stined at 25 °C for 4h and quenched with 10% ⁇ aHSO 3 .
  • the mixture was extracted with ethyl acetate, the solvents were evaporated, and the residue was purified using 5%> methanol/dichloromethane to give 21 mg (67%) ofthe title compound.
  • Example 764 (2S)-N- ⁇ (lS,2R)-l-benzyl-3-[[(4-formylphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl ⁇ - 3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl ⁇ butanamide
  • Example 749 (81 mg, 0.12 mmol) in tetrahydrofuran (3 mL) and water (0.6 mL) was added 4% weight OsO 4 in water (44 ⁇ L, 6 mol%) followed by ⁇ aIO 4 (56 mg, 2.2 equivalents).
  • Example 765 (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[ ⁇ [4- (hydroxymethyl)phenyl]sulfonyl ⁇ (isobutyl)amino]propyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl ⁇ butanamide
  • Example 764 (14 mg, 0.02 mmol) was dissolved in ethanol (0.5 mL) and combined with ⁇ aBH 4 (2.2 mg, 3 equivalent) and stined at 25 °C for 1 h.
  • Example 766 (2S)-N- ⁇ (lS,2R)-l-benzyl-3-[ ⁇ [4-(formylamino)phenyl]sulfonyl ⁇ (isobutyl)amino]-2- hydroxypropyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl ⁇ butanamide
  • Example 650 (10 mg, 0.014 mmol) was dissolved in tetrahydrofuran (0.25 mL) and combined with formic acetic anhydride (2 drops) and the mixture was stined for 1 h. The solvent was evaporated, and the residue was purified by using 5% methanol/dichloromethane to give 8.5 mg (83%>) ofthe title compound.
  • Example 767 (2S)-N- ⁇ (lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l -benzyl-2- hydroxypropyl ⁇ -2-(3 - ⁇ [2-(hydroxymethyl)- 1 ,3 -thiazol-4-yl]methyl ⁇ -2-oxo- 1 - imidazolidinyl)-3-methylbutanamide
  • Example 687 (45 mg, 0.059 mmol) was dissolved in water: tetrahydrofuran (1 mL, 2:1) and treated with lithium hydroxide (8 mg, 3 equivalents) at 25 °C for 30 min.
  • Example 768A (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- nitrophenyl)sulfonyl](isobutyl)amino]propyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl ⁇ butanamide
  • dichloromethane 1.2 mL
  • bistrimethylsilylacetamide 72 ⁇ L, 1 equivalent
  • Example 713B 150 mg, 1 equivalent
  • triethylamine (0.12 mL, 3 equivalents).
  • the mixture was stined for 16 h, and the solvents were evaporated.
  • the crude residue was treated with tetrabutylammonium fluoride (TBAF) (0.9 mL, 3 equivalents IM tetrabutyl ammonium fluoride/tetrahydrofuran) for 2 h and the solvents were evaporated.
  • TBAF tetrabutylammonium fluoride
  • the residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%>) to give 132 mg (62%) ofthe title compound.
  • Example 768B (2S)-N- ⁇ (lS,2R)-3-[[(3-amino-4-hydroxyphenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl ⁇ butanamide
  • Example 768A (132 mg, 0.184 mmol) in ethanol/acetic acid (2 mL, 1 : 1) is added Fe powder (40 mg, 4 equivalents) at 70 °C for 2 h. The mixture was evaporated and partitioned between CHC1 and 10%> EDTA disodium salt. The organic layer was washed with brine, dried over MgSO 4 , filtered, and evaporated to give 112 mg (90%> crade yield) ofthe title compound.
  • Example 773 (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl( ⁇ 4- [(methoxyimino)methyl]phenyl ⁇ sulfonyl)amino]propyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl ⁇ butanamide
  • Example 764 (14.7 mg, 0.022 mmol) was dissolved in ethanol (0.5 mL) and treated with ⁇ , ⁇ -diisopropylethylamine (6.1 ⁇ L, 2.2 equivalents) and hydroxylamine-O-methyl ether hydrochloride (3.6 mg, 2 equivalents) at 25 °C for 2 h. The mixture was partitioned between IN NaHCO 3 and ethyl acetate. The organic layer was evaporated, and the residue was purified using 5% methanol/chloroform to give
  • Example 774 (2S)-N- ⁇ (lS,2R)-l-benzyl-3-[(2,3-dihydro-lH-indol-5-ylsulfonyl)(isobutyl)amino]-2- hydroxypropyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl ⁇ butanamide
  • Example 693 25 mg, 0.034 mmol was dissolved in methanol (2 mL) and treated with IN HCI (3 mL) at 60 °C for 5 h. The solvents were evaporated, and the residue was purified using 5%> methanol/dichloromethane to give 12 mg (51%) ofthe title compound.
  • Example 775 (2S)-N- ⁇ (lS,2R)-l-benzyl-3-[(2,3-dihydro-lH-indol-5-ylsul
  • Example 776 (2S)-N- ⁇ (lS,2R)-3-[( ⁇ 3-[(3-aminopropanoyl)amino]-4- hydroxyphenyl ⁇ sulfonyl)(isobutyl)amino]-l -benzyl-2-hydro ⁇ ypropyl ⁇ -3-methyl-2- ⁇ 3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl ⁇ butanamide
  • Example 772 (10 mg, 0.012 mmol) was dissolved in dichloromethane (0.2 mL) and trifluoroacetic acid (0.1 mL), and the mixture was stined at 25 °C for 1 h.
  • Example 777A (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3- ⁇ isobutyl[(3-nitrophenyl)sulfonyl]amino ⁇ propyl)-3- methyl-2- ⁇ 3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl ⁇ butanamide
  • Example 713B 50 mg, 0.097 mmol
  • dichloromethane (1 mL) and treated with 3-nitrobenzenesulfonyl chloride (26 mg, 1.2 equivalents) and triethylamine (27 ⁇ L, 2 equivalents) at 25 ° for 18 h.
  • the solvents were evaporated and the crude residue was purified using chloroform - chloroform/2%) methanol to give 66.8 mg (97%) ofthe title compound.
  • Example 777B tert-butyl 2-(3- ⁇ [ ⁇ (2R,36)-2-hydroxy-3-[((2S)-3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4- yl)methyl] -2-oxo- 1 -imidazolidinyl ⁇ butanoyl)amino]-4- phenylbutyl ⁇ (isobutyl)amino]sulfonyl ⁇ anilino)-2-oxoethylcarbamate
  • Example 777A (66 mg, 0.094 mmol) was dissolved in ethanol: acetic acid (1 mL, 1:1) and treated with iron powder (21 mg, 4 equivalents) at 70 °C for 1.5 h.
  • Example 778 (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[ ⁇ [3- (hydroxymethyl)phenyl]sulfonyl ⁇ (isobutyl)amino]propyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl- 1,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl ⁇ butanamide
  • Example 758 (88 mg, 0.123 mmol) was dissolved in dichloromethane (1 mL) and treated with diisobutyl aluminum hydride (0.62 mL, 5 equivalents, IM solution in dichloromethane) at -78 °C for 1 h.
  • Example 779 (2S)-N- ⁇ (lS,2R)-l-benzyl-3-[[(5-fomyl-2-furyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide
  • Example 757 (103 mg, 0.134 mmol) in acetonitrile (1 mL) at 0 °C was added trimethylsilyl iodide (0.2 mL, 10 equivalents).
  • Example 780 (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 5-[(E)-(hydroxyimino)methyl]-2- furyl ⁇ sulfonyl)(isobutyl)amino]propylJ-3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo- 1 -imidazolidinyl ⁇ butanamide
  • Example 780A (2S)-N-[(lS,2R)-l-benzyl-2-hydroxy-3-(isobutyl ⁇ [5-( ⁇ [(4-nitrobenzyl)oxy]imino ⁇ methyl)-2- furyl] sulfonyl ⁇ amino)propyl]-3 -methyl-2- ⁇ 3- [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyl ⁇ butanamide
  • Example 780B (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 5-[(E)-(hydroxyimino)methyl]-2- furyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo-l-imidazolidinyl ⁇ butanamide
  • Examples 781 (2S)-N- ⁇ (lS,2R)-l-benzyl-2-hydroxy-3-[( ⁇ 5-[(Z)-(hydroxyimino)methyl]-2- furyl ⁇ sulfonyl)(isobutyl)amino]propyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl- 1
  • Example 780B The mixture was cooled, evaporated, and partitioned between CHC1 3 and 10%> EDTA. The organic layer was dried over ⁇ a 2 SO 4 , filtered, and evaporated. The residue was purified using ethyl acetate: hexanes (3:1) to give 11 mg (22% 0 ) of Example 780B and 12 mg (24%) of Example 781.
  • Example 783 4- ⁇ [ ⁇ (2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo- l-imidazolidinyl ⁇ butanoyl)amino]-4-phenylbutyl ⁇ (isobutyl)amino]sulfonyl ⁇ benzamide
  • Example 721 (33 mg, 0.048 mmol) was dissolved in ethanol (1 mL) and treated with triethylamine (70 ⁇ L, 10 equivalents) and hydroxylamine hydrochloride (14 mg, 4 equivalents). The mixture was heated at 50 °C for 3 hrs. The solvents were evaporated, and the residue was purified using 5% methanol/dichloromethane to give 13 mg (37%) of Example 782 and 8.5 mg (25%) of Example 783.
  • Example 784 4- ⁇ [[(2R,3S)-2-hydroxy-3-( ⁇ (2S,3S)-3-methyl-2-[2-oxo-3-(3-pyridinylmethyl)-l- imidazolidinyl]pentanoyl ⁇ amino)-4-phenylbutyl](isobutyl)amino]sulfonyl ⁇ benzamide
  • Example 785 (36 mg, 0.053 mmol) was dissolved in methanol (1 mL) and treated with triethylamine (75 ⁇ L, 10 equivalents) and hydroxylamine hydrochloride (15 mg, 4 equivalents). The mixture was heated to 80 °C for 1 h. The solvents were evaporated, and the residue was purified using 8% methanol/ethyl acetate to give 20 mg (53%>) of the p- hydroxyamidine and 4 mg (11%>) ofthe title compound.
  • Example 785A (2S,3S)-N-[(lS,2R)-l-benzyl-2-hydroxy-3-(isobutylamino)propyl]-3-methyl-2-[2-oxo-3-(3- pyridinylmethyl)- 1 -imidazolidinyljpentanamide
  • Example 103 (0.266 g, 0.9 mmol) was combined with Example 713A (0.153 g, 1 equivalent) in ⁇ , ⁇ -dimethylformamide (2 mL) and to this mixture was added HOBT (0.1 g, 1.5 equivalents) and EDAC (0.15 g, 1.5 equivalents).
  • Example 785B (2S,3S)-N- ⁇ (lS,2R)-l-benzyl-3-[[(4-cyanophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl ⁇ -3-methyl-2-[2-oxo-3-(3-pyridinylmethyl)-l-imidazolidinyl]pentanamide
  • Example 785A 50 mg, 0.098 mmol
  • y?-cyanobenzenesulfonyl chloride 24 mg, 1.2 equivalents
  • triethylamine 41 ⁇ L, 3 equivalents
  • Example 786 (2S)-N- ⁇ (1S,2R)- 1 -benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl ⁇ -2- ⁇ 3-[(2-ethyl-l,3-thiazol-4-yl)methyl]- 2,4-dioxo-l-imidazolidinyl ⁇ -3-methylbutanamide
  • Example 290 (75 mg, 0.23 mmol ) was combined with N-hydroxysuccinimide (24.8 mg, 1.1 equivalents) and DCC (44.5 mg, 1.1 equivalents) in dichloromethane (1 mL) and stined for 1 h at 25° C.
  • Example 372 (78 mg, 0.1 mmol ) was dissolved in dichloromethane (1 mL) and treated with Boc- ⁇ -alanine hydroxysuccinimide ester (45 mg, 1.4 equivalents), ⁇ - methylmorpholine (25 ⁇ L, 2 equivalents) and DMAP (20 mg, 1.4 equivalents) at 25 °C for 18
  • Example 844B (2S)-N- ⁇ (lS,2R)-3-[ ⁇ [4-((E)- ⁇ [(3- aminopropanoyl)oxy]imino ⁇ methyl)phenyl]sulfonyl ⁇ (cyclopentylmethyl)amino]-l-benzyl-2- hydroxypropyl ⁇ -3-methyl-2- ⁇ 3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l- imidazolidinyl ⁇ butanamide
  • Example 844A (60 mg, 0.066 mmol) was dissolved in dichloromethane: trifluoroacetic acid (3 mL, 2:1) at 25 °C for 30 min.

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Abstract

A compound of the formula (I) is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.

Description

HIV PROTEASE INHIBITING COMPOUNDS
Technical Field The present invention relates to novel compounds and a composition and a method for inhibiting human immunodeficiency virus (HIN) protease, a composition and method for inhibiting or treating an HIN infection, processes for making the compounds and synthetic intermediates employed in the processes.
Background of the Invention The genome of the human immunodeficiency virus (HIN) encodes a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. HIN protease processes the gag precursor into core proteins and also processes the pol precursor into reverse transcriptase and protease. The correct processing of the precursor polyproteins by HIN protease is necessary for the assembly of infectious virions. Therefore, inhibition of HIN protease provides a useful target for development of therapeutic agents for treatment of HIN infection. In recent years, inhibitors of HIN protease have become an important class of therapeutic agents for inhibition and treatment of HIN infection in humans. HIN protease inhibitors are especially effective when administered in combination with other classes of HIN therapeutic agents, especially inhibitors of HIN reverse transcriptase, in "cocktails" of HIV therapeutic agents. At the present time, the HIN protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir/ritonavir, fosamprenavir, and atazanavir have been approved in the U.S. for treatment of HIN infection. There is a continuing need for improved HIV protease inhibitors that are very potent, that have reduced side-effects and that are effective against resistant strains of HIV.
Summary of the Invention The present invention provides a compound of formula (I)
Figure imgf000002_0001
(I) or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, wherein:
Figure imgf000003_0001
X is O, S orNH; Y is O, S orNH;
R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl or heteroarylalkyl; wherein each R is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, formyl, nitro, hydroxy, alkoxy, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, haloalkyl, hydroxyalkyl and alkoxyalkyl; Rj is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rla)NRaRb or -OC(=O)C(H)(Rla)N(H)C(O)ORa; Rla is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each Rla is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaRb, -C(=O)Ra, -NRaR , -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Ra)SO2NRaRb, -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaRb and -C(=O)ORa; R2 is H;
R3 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra, -alkylNRaRb, -alkylN(Rb)C(=O)ORa, -alkylN(Rb)C(=O)Ra, -alkylN(R )SO2Ra or -alkylN(Rb)SO2NRaRb; wherein each of the cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the cycloalkenylalkyl, hetrocycle moiety of the heterocyclealkyl, heteroaryl moiety of the heteroarylalkyl, aryl moiety of the arylalkyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), - N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2, -alkylC(==O)alkyl and R3a; R3a is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, wherein each R3a is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2 and -alkylC(=O)alkyl; R4 is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl wherein each R4 is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, alkyl, oxo, alkenyl, alkynyl, nitro, cyano, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, nitroalkyl, -OR4a,
Figure imgf000004_0001
-C(=O)NR4aR4b, -N(R4 )C(-O)R4a, -N(R4b)C(=O)OR4a, -N(R4b)SO2R4a, -N(R4b)C(=O)NR4aR4 , -N(R4b)SO2NR4aR4b, -alkylSR4a, -alkylSOR^, -alkylSO^a,
-alkylNR4aR4 , -alkylOC(=O)R4a, -alkylC(=O)R4a, -alkylC(=O)OR4a, -alkylC(=O)NR4aR4 , -alkylN(R4 )C(=O)R4a, -alkylN(R4b)C(=O)OR4a, -alkylN(R4b)SO2R4a, -al^lN(R4 )C(=O)NR4aR4b, -alkylN(R4b)SO2NR4aR , -N(H)C(=O)alkylN(H)C(=O)OR4a, -N(H)C(-O)alkylNR4aR4b, -C(R4b)=NOR4a, -C(NR4aR4b)=NOR4a and -C(R4b)=NOC(=O)alkylNR4aR4 ; ^a and ^, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl and heteroalkyl; wherein each R^ and R4b, at each occurrence, is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, hydroxy, alkoxy, halo, nitro, cyano, formyl, oxo, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)alkyl, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)alkyl, -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, cyanoalkyl, nitroalkyl, formylalkyl and alkoxyalkyl; R5 is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -OalkylSO alkyl, -O-heterocycle, -alkyl-O-aryl or -O-alkyl-heteroaryl; wherein the heterocycle, aryl or heteroaryl moiety of -O-heterocycle, -alkyl-O-aryl and -O-alkyl-heteroaryl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2; R6 is aryl or heteroaryl; wherein each R6 is substituted with 0 or 1 substituent selected from the group consisting of -C(H)=NOH, -C(alkyl)=NOH, -C(H)=NO(alkyl), -C(alkyl)=NO(alkyl), -C(H)=NO(arylalkyl) and -C(alkyl)=NO(arylalkyl); R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; wherein each R is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, -ORa, -OalkylC(=O)NRaR , -SRa, -SORa, -SO2Ra, -SO2NRaRb, -C(=O)Ra, - RaR , -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Rb)SO2NRaRb, -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(-O)NRaRb, -C(=O)ORa and R7a; R7a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R7a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OHJ -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2; R8 is -C(=O)OR8a or -C(=O)alkylNR8aR8 ,
R8a and R8b are, at each occurrence, independently selected from the group consisting of alkyl, arylalkyl and heteroarylalkyl; wherein each R8a and R8b is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of alkyl, nitro, hydroxy, alkoxy, amino, formyl, halo, haloalkyl, hydroxyalkyl, alkoxyalky aminoalkyl and formylalkyl;
R9 is ailcyl, alkenyl, alkynyl, -C(=O) RaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R9 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb,
-N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaRb, -N(Rb)SO2NRaRb, -C(=O)Ra, -C(=O)NRaR , -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaR , -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(alkyl)=NNRaRb, -C(H)(=NORa)NRaRb, -C(alkyl)(=NORa)NRaR , -alkylN(Rb)NRaRb, -alkylN(Rb)C(=O)Ra, -alkylN(Rb)C(=O)ORa, -alkylN(R )C(=O)NRaRb, -alkylN(Rb)SO2 RaRb, -alkylN(Rb)SO2Ra, -alkylC(=O)Rβ, -alkylC(=O)ORa, -alkylC(=O)NRaRb and R9a;
R9a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R9a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -aIkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
R10 is alkyl, alkenyl, alkynyl, -C(=O)NRaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R10 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb,
-N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaR , -N(R )SO2NRaR , -C(=O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2 Ra, -alkylSO2ORa, -alkylNRaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(alkyl)=NNRaR , -C(H)(=NORa)NRaRb, -C(alkyl)(=NORa)NRaR , -alkylN(R )NRaRb, -alkylN(Rb)C(=O)Ra, -alkylN(R )C(=O)ORa, -alkylN(Rb)C(=O)NRaRb, -alkylN(R )SO2NRaR , -alkylN(Rb)SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaR and R10a; R10a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each Rι0a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH , -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(allcyl)2, -alkylC(==O)OH, -alkylC(=O)0alkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and
-alkylC(=O)N(alkyl)2;
Rπ is alkyl, alkenyl, alkynyl, -C(=O)NRaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each Rπ is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SR* -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaR , -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaR , -N(R )SO2NRaRb, -C(=O)Ra, -C(=O)NHaR , -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb,
-C(alkyl)=NNRaR , -C(H)(=NORa)NRaR , -C(alkyl)(=NORa)NRaR , -alkylN(Rb)NRaRb, -alkylN(R )C(=O)Ra, -alkylN(Rb)C(=O)ORa, -alkylN(R )C(=O)NRaR , -alkylN(R )SO2NRaR , -alkylN(R )SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaRb and Rlla; Rπa is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R\ la is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(-O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2; R12 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or cycloalkenylalkyl; wherein each R12 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, alkoxy cyano, nitro and halo;
R13 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R13 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb, -N(R )NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(R )C(=O)ORa, -N(Rb)C(=O)NRaRb, -N(Rb)SO2NRaRb, -C(=O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra3-alkylSO2NRa, -alkylSO2ORa, -alkyl RaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(alkyl)=N RaR ,
-C(H)(=NORa)NRaRb, -C(alkyl)(=NORa)NRaR , -alkylN(Rb)NRaR , -alkylN(Rb)C(=O)Ra, -alkylN(Rb)C(=O)ORa, -alkylN(R )C(=O)NRaRb, -alkylN(Rb)SO2NRaRb, -alkylN(Rb)SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaR and R13a; R13a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R13a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(-O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle; wherein each Ra and Rb, at each occurrence, is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(-O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(-O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 a d Rc; alternatively, Ra and Rb, together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(-O)N(alkyl)2 and Re; Re is aryl, heteroaryl or heterocycle; wherein each Re is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)2, -alkyl-N(H)C(=O)NH2, -alkyl-N(H)C(=O)N(H)(alkyl), -alkyl-N(H)C(=O)N(alkyl)2, -alkyl-C(=O)OH, -alkyl-C(=O)Oalkyl, -alkyl-C(=O)NH2, -alkyl-C(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2; and n is 1 or 2. The present invention also provides the processes of making a compound of the present invention and intermediates employed in the processes. The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, and a pharmaceutically acceptable carrier. The present invention yet further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, and one, two, three, four, five or six agents selected from the group consisting of a second HIV protease inhibitor, a HIV reverse transcriptase inhibitor, an HIV entry/fusion inhibitor, an HIV integrase inhibitor and an HIV budding/maturation inhibitor, and a pharmaceutically acceptable carrier. The present invention still further provides a method of inhibiting the replication of an
HIV virus comprising contacting said virus with a therapeuctially effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof. The present invention still further provides a method of inhibiting the replication of an
HIV virus comprising contacting said virus with any one of the pharmaceutical composition of the present invention. The present invention still further provides a method of inhibiting an HIV protease comprising contacting said HIV protease with a therapeuctially effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof. The present invention still further provides a method of inhibiting an HIV protease comprising contacting said HIV protease with any one of the pharmaceutical composition of the present invention. The present invention also provides a method of treating or preventing an HIV infection comprising administering to a patient in need of such treatment a therapeuctially effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof. The present invention also provides a method of treating or preventing an HIV infection comprising administering to a patient in need of such treatment any one of the phannaceutical composition of the present invention.
Detailed Description of the Invention As used in the present specification the following terms have the meanings indicated: As used herein, the singular forms "a", "an", and "the" may include plural reference unless the context clearly dictates otherwise. The term "activated carboxylic acid group" as used herein refers to acid halides such as acid chlorides and also refers to activated ester derivatives including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, anhydrides derived from reaction of the carboxylic acid with N,N'-carbonyldiimidazole and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N- hydroxy-5-norbornene-2,3-dicarboximide derived esters, 2,4,5-trichlorophenol derived esters, p-nitrophenol derived esters, phenol derived esters, pentachlorophenol derived esters, 8- hydroxyquinoline derived esters and the like. The term "alkanoyl" as used herein refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of alkanoyl include methylcarbonyl, ethylcarbonyl, tert-butylcarbonyl and the like. The term "alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Examples of alkyl groups include butyl, methyl, 1-methylpropyl, 2-methylbutyl, tert-butyl, isopropyl, and the like. The term "alkylamino" as used herein refers to -N(H)R90 wherein R90 is alkyl. The term "alkylaminocarbonyl" as used herein refers to an alkylamino group attached to the parent molecular moiety through a carbonyl group. The term "alkenyl," as used herein, refers to a straight or branched chain group of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms containing at least one carbon-carbon double bond. Examples of alkenyl groups include allyl, propenyl, 3-methyl-2-butenyl, and the like. The term "alkynyl," as used herein, refers to a straight or branched chain hydrocarbon of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms containing at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl, 2-methyl-3-butynyl, 3-pentynyl, and the like. The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom. Examples of alkoxy groups include tert-butoxy, methoxy, isopropoxy, and the like. The term "alkoxyalkyl," as used herein, refers to an alkyl group substituted by at least one alkoxy group. The term "alkoxycarbonyl," as used herein, refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl groups include tert-butoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, and the like. The term "amino" as used herein, refers to -NH2. The term "aminoalkyl" as used herein, refers to an amino group appended to the parent molecular moiety through an alkyl group as defined herein. The term "aryl" as used herein, refers to a phenyl group, or a bicyclic or tricyclic hydrocarbon fused ring systems wherein one or more of the rings is a phenyl group. Bicyclic fused ring systems have a phenyl group fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group. Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group. Examples of aryl groups include anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like. The aryl groups of the present invention can be connected to the parent molecular moiety through any substitutable carbon atom of the group. The aryl groups of the present invention can be substituted or unsubstituted. The term "arylalkyl," as used herein, refers to an aryl group attached to the parent molecular moiety through an alkyl group. The term "carbonyl" as used herein, refers to -C(=O). The term "cyano," as used herein, refers to -CN. The term "cyanoalkyl," as used herein, refers to a cyano group attached to the parent molecular moiety through an alkyl group. The term "cycloalkenyl," as used herein, refers to a non-aromatic, partially unsaturated, monocyclic, bicyclic or tricyclic ring system, having three to fourteen carbon atoms and zero heteroatom. Examples of cycloalkenyl groups include cyclohexenyl, octahydronaphthalenyl, norbornylenyl, and the like. The cycloalkenyl groups of the present invention can be unsubstituted or substituted. The term "cycloalkenylalkyl," as used herein, refers to a cycloalkenyl group attached to the parent molecular moiety through an alkyl group. The term "cycloalkyl," as used herein, refers to a saturated monocyclic, bicyclic.; or tricyclic hydrocarbon ring system having three to fourteen carbon atoms and zero heteroatom. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[3.1.1]heptyl, 6,6-dimethylbcyclo[3.1.1]heptyl, adamantyl, and the like. The cycloalkyl groups of the present invention can be unsubstituted or substituted. The term "cycloalkylalkyl," as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through an alkyl group. The term "dialkylamino" as used herein refers to -NR90R91, wherein R90 and R91 are alkyls. The term "dialkylaminocarbonyl" as used herein refers to a dialkylamino group as defined herein, appended to the parent molecular moiety through a carbonyl group. The term "formyl", as used herein, refers to a -C(O)H group. The term "formylalkyl" as used herein, refers to a formyl group appended to the parent molecular moiety through an alkyl group. The terms "halo," and "halogen," as used herein, refer to F, CI, Br, and I. The term "haloalkenyl," as used herein, refers to an alkenyl group substituted by one, two, three, or four halogen atoms. The term "haloalkoxy" as used herein, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. The term "haloalkoxyalkyl" as used herein, refers to a haloalkoxy group attached to the parent molecular moiety through an alkyl group, as defined herein. The term "haloalkyl," as used herein, refers to an alkyl group substituted by one, two, three, or four halogen atoms. The term "haloalkynyl," as used herein, refers to an alkynyl group substituted by one, two, three, or four halogen atoms. The term "heteroaryl," as used herein, refers to an aromatic five- or six-membered ring where at least one atom is selected from the group consisting of N, O, and S, and the remaining atoms are carbon. The term "heteroaryl" also includes bicyclic systems where a heteroaryl ring is fused to a phenyl group, a monocyclic cycloalkyl group, as defined herein, a heterocycle group, as defined herein, or an additional heteroaryl group. The term "heteroaryl" also includes tricyclic systems where a bicyclic system is fused to a phenyl group, a monocyclic cycloalkyl group, as defined herein, a heterocycle group, as defined herein, or an additional heteroaryl group. The heteroaryl groups are connected to the parent molecular moiety through any substitutable carbon or nitrogen atom in the groups. Examples of heteroaryl groups include benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, benzofuranyl, dihydrobenzothiazolyl, furanyl (furyl), imidazolyl, 3H-[4,5-b]pyridinyl, indazolyl, indolyl, isoindolyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, oxazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, tetrazolyl, pyridoimidazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, tetrahydroquinolinyl, triazinyl, and the like. The heteroaryl groups of the present invention can be substituted or unsubstituted. In addition, the nitrogen heteroatoms can be optionally quatemized or oxidized to the N-oxide. Also, the nitrogen containing rings can be optionally N-protected. The term "heteroarylalkyl", as used herein, refers to refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group. The term "heterocycle," as used herein, refers to cyclic, non-aromatic, saturated or partially unsaturated, three, four, five-, six-, or seven-membered rings containing at least one atom selected from the group consisting of oxygen, nitrogen, and sulfur. The term "heterocycle" also mcludes bicyclic systems where a heterocycle ring is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or an additional monocyclic heterocycle group. The term "heterocycle" also includes tricyclic systems where a bicyclic system is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or an additional monocyclic heterocycle group. The heterocycle groups of the invention are connected to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group. Examples of heterocycle groups include benzoxazinyl, 1,3- benzodioxol, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, tetrahydrofuranyl, hexahydrofurofuranyl, hexahydrofuropyranyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomoipholinyl, tetrahydropyranyl, and the like. The heterocycle groups of the present invention can be substituted or substituted. In addition, the nitrogen heteroatoms can be optionally quatemized or oxidized to the N-oxide. Also, the nitrogen containing heterocyclic rings can be optionally N-protected. The term "heterocyclealkyl", as used herein, refers to refers to a heterocycle group attached to the parent molecular moiety through an alkyl group. The term "hydroxy" or "hydroxyl" as used herein, refers to -OH. The term "hydroxyalkyl," as used herein, refers to an alkyl group as substituted by at least one hydroxy group. The term "nitro," as used herein, refers to -NO . The term "nitroalkyl," as used herein, refers to an alkyl group substituted by at least one nitro group. The term "oxo," as used herein, refers to =O. The term "thioalkoxy", as used herein, refers to an alkyl group as defined herein, appended to the parent molecular moiety through a sulfur atom. The term "thioalkoxyalkyl", as used herein, refers to an thioalkoxy group as defined herein, appended to the parent molecular moiety through a alkyl group. It is understood that each of the terms alkanoyl, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkynyl, aminoalkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, dialkylamino, dialkylaminocarbonyl, formylalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkynyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, nitroalkyl, thioalkoxy and thioalkoxyalkyl may be unsubstituted or substituted. In a first embodiment, the present invention provides a compound of formula (I),
Figure imgf000014_0001
(I) or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, wherein: A is R5C(O , R6SO2-,
Figure imgf000014_0002
X is O, S or NH; Y is O, S or NH; R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl or heteroarylalkyl; wherein each R is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, formyl, nitro, hydroxy, alkoxy, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, haloalkyl, hydroxyalkyl and alkoxyalkyl; R! is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rla)NRaRb or -OC(=O)C(H)(Rla)N(H)C(O)ORa;
Rla is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each Rla is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaR , -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Ra)SO2NRaR , -N(R )C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaR and -C(=O)ORa; R2 is H;
R3 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra, -alkylNRaRb, -alkylN(Rb)C(=O)ORa, -alkylN(R )C(=O)Ra, -alkylN(R )SO2Ra or -alkylN(Rb)SO2NRaRb; wherein each of the cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the cycloalkenylalkyl, hetrocycle moiety of the heterocyclealkyl, heteroaryl moiety of the heteroarylalkyl, aryl moiety of the arylalkyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), - N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alky IS (alkyl), -alkylSO2(alkyl), -alkylNH2, -alkyϊN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2, -alkylC(=O)alkyl and R3a; R a is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, wherein each R3a is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2 and -alkylC(=O)alkyl; Rj is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl wherem each i is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, alkyl, oxo, alkenyl, alkynyl, nitro, cyano, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, nitroalkyl, -O ia, -SR^, -SOR^, -SO2Rta, -M JE b, -OC(=O)R4a, -C(=O)R4a, -C(=O)OR4a,
Figure imgf000015_0001
-N(R4 )C(=O)NR4aR4b, -N(R4b)SO2NR4aR4b, -alkylSR4a, -alkylSOI^a, -alkylSORa,
-alkyl E^ta n,, -alkylOC(=O)R4a, -alkylC(=O)R4a, -alkylC(=O)OR a, -alkylC(=O)NR aR4b, -allcylN(R4b)C(=O)R4a, -alkylN(R4b)C(=O)OR4a, -alkylN(R4b)SO2R4a,
Figure imgf000016_0001
-N(H)C(=O)alkylNR4aR4b, -C(R4 )=NOR4a, -C(NR4aR4b)=NOR4a and -C(R4b)=NOC(=O)alkylNR4aR4 ;
R4a and R4b, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl and heteroalkyl; wherein each ta and Rn,, at each occurrence, is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, hydroxy, alkoxy, halo, nitro, cyano, formyl, oxo, -NH , -N(H)alkyl, -N(alkyl)2, -C(=O)alkyl, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)alkyl, -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, cyanoalkyl, nitroalkyl, formylalkyl and alkoxyalkyl;
R5 is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -OalkylSO2alkyl, -O-heterocycle, -alkyl-O-aryl or -O-alkyl-heteroaryl; wherein the heterocycle, aryl or heteroaryl moiety of -O-heterocycle, -alkyl-O-aryl and -O-alkyl-heteroaryl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl) , cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(0)N(H)(alkyl) and -alkylC(=O)N(alkyl)2; R6 is aryl or heteroaryl; wherein each R6 is substituted with 0 or 1 substituent selected from the group consisting of-C(H)=NOH, -C(alkyl)=NOH, -C(H)=NO(alkyl), -C(alkyl)=NO(alkyl), -C(H)=NO(arylalkyl) and -C(alkyl)=NO(arylalkyl); R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; wherein each R7 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, -ORa,
Figure imgf000016_0002
-SRa, -SORa, -SO2Ra, -SO2NRaRb, -C(=O)Ra, -NRaRb, -N(R )C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Rb)SO2NRaR , -N(Rb)C(=NH)NRaR , -N(Rb)C(=O)NRaRb, -C(=O)NRaRb, -C(=O)ORa and R7a; R7a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R7a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyI)2; R8 is -C(=O)OR8a or -C(=O)alkylNR8aR8b, R8a and R8b are, at each occurrence, independently selected from the group consisting of alkyl, arylalkyl and heteroarylalkyl; wherein each R8a and R8b is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of alkyl, nitro, hydroxy, alkoxy, amino, formyl, halo, haloalkyl, hydroxyalkyl, alkoxyalky aminoalkyl and formylalkyl; R9 is alkyl, alkenyl, alkynyl, -C(=O)NRaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R9 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaR , -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaRb, -N(R )SO2NRaR , -C(=O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaRb, -C(H)-N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(alkyl)=NNRaRb, -C(H)(=NORa)NRaRb, -C(alkyl)(=NORa)NRaR , -alkylN(Rb)NRaR , -alkylN(Rb)C(=O)Ra, -alkylN(R )C(=O)ORa, -alkylN(R )C(=O)NRaRb, -alkylN(Rb)SO2NRaRb, -alkylN(R )SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaR and R9a;
R9a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R9a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), ralkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
R10 is alkyl, alkenyl, alkynyl, -C(=O)NRaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R10 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb,
-N(Rb)NRaRb, -N(R )C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaR , -N(R )SO2NRaRb, -C(=O)Ra, -C(=O)NRaR , -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(alkyl)=NNRaRb, -C(H)(=NORa)NRaR , -C(alkyl)(=NORa)NRaRb, -alkylN(Rb)NRaRb, -alkylN(Rb)C(=O)Ra, -alkylN(Rb)C(=O)ORa, -alkylN(Rb)C(=O)NRaRb, -alkylN(Rb)SO2NRaR , -alkylN(R )SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaR and R10a;
R10a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R10a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(-O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
Rπ is alkyl, alkenyl, alkynyl, -C(=O)NRaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each Rπ is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb,
-N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(-O)ORa, -N(Rb)C(=O)NRaR , -N(R )SO2NRaRb, -C(-O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(aιkyl)=NNRaRb, -C(H)(=NORa)NRaR , -C(alkyl)(=NORa)NRaRb, -alkylN(R )NRaR , -alkylN(R )C(=O)Ra, -alkylN(R )C(=O)ORa, -alkylN(Rb)C(-O)NRaRb, -alkylN(R )SO2NRaRb, -alkylN(R )SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaRb and Rl la; Riia is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each Rlla is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH , -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
R12 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or cycloalkenylalkyl; wherein each R12 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, alkoxy cyano, nitro and halo;
R13 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R13 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb, -N(Rb)NRaR , -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaRb, -N(Rb)SO2NRaRb, -C(=O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(alkyl)=NNRaRb, -C(H)(-NORa)NRaR , -C(alkyl)(=NORa)NRaRb, -alkylN(Rb)NRaRb, -alkylN(Rb)C(=O)Ra, -alkylN(R )C(=O)ORa, -alkylN(R )C(=O)NRaRb, -alkylN(R )SO2NRaRb, -alkylN(R )SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaR and R13a; Ri3a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R13a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(==O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(0)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2,
Figure imgf000019_0001
-alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle; wherein each Ra and Rb, at each occurrence, is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2,
-alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Re; alternatively, Ra and Rb, together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH,
-C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH , -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=0)NH2, -alkylC(=0)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and R-;
Re is aryl, heteroaryl or heterocycle; wherein each R- is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), ' -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyI), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)2, -alkyl-N(H)C(=O)NH2, -alkyl-N(H)C(=O)N(H)(alkyl), -alkyl-N(H)C(=O)N(alkyI)2, -alkyl-C(=O)OH, -alkyl-C(=O)Oalkyl, -alkyl-C(=O)NH2, -alkyl-C(-O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2; and n is 1 or 2. For example, the present invention provides a compound of formula (I) wherein Ri is OH and R2 is H. For example, the present invention provides a compound of formula (I) wherein R\ is OH, R2 is H, X is O and Y is O. For example, the present invention provides a compound of formula (I) wherein wherein R\ is OH, R is H, X is O, Y is O, and R3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra or -alkylNRaRb. For example, the present invention provides a compound of formula (I) wherein R\ is OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkylalkyl and R4 is aryl or heteroaryl. For example, the present invention provides a compound of formula (I) wherein R1 is OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkylalkyl and i is phenyl. For example, the present invention provides a compound of formula (I) wherein R1 is OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkylalkyl and Rt is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -O ia, -NR a 4b and
-C(R4b)=NOR4a; wherein R^ and R^ are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (I) wherein ! is OH, R2 is H, R3 is alkyl or cycloalkylalkyl, I is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -O ^a, -NR aR b and -C(R4b)=NOR a, and R is phenylmethyl wherein R4a and u, are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (I) wherein Ri is OH, R2 is H, R3 is alkyl or cycloalkylalkyl, R4 is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR4a, -NR^R^ and -C^^NOR^, R is phenylmethyl and R7 is alkyl; wherein R^ and n, are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (I) wherein Ri is OH, R2 is H, R3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentyhnethyl, R4 is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORia,
Figure imgf000021_0001
R is phenylmethyl and R7 is alkyl; wherein R a and R are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (I) wherein Ri is OH, R2 is H, R3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentyhnethyl, R4 is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -O ^, - taRft and -C(R4b)=NOR a, R is phenylmethyl and R is CI alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5 alkyl; wherein ia and R are independently selected from the group consisting of hydrogen and alkyl. Exemplary compounds of the present invention having formula (I) include, but not limited to, the following: hexahydrofuro[2,3-b]furan-3-yl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- '
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; tetrahydro-3-furanyl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} acetamide; N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-(2,6- dimethylρhenoxy)acetamide; (3aS,7aR)-hexahydro-4H-furo[2,3-b]pyran-3-yl (lS,2R)-l-benzyl-2-hydroxy-3-[({4- [(E)-(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propylcarbamate and
(3aR,7aS)-hexahydro-4H-furo[2,3-b]pyran-3-yl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; 3-furylmethyl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; 2-pyridinylmethyl 2-({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]ρhenyl}sulfonyl)(isobutyl)amino]ρropyl}amino)-2- oxoethylcarbamate; 2-(methylsulfonyl)ethyl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; (3aS,7aR)-hexahydro-4H-furo[2,3-b]pyran-3-yl (lS,2R)-l-benzyl-2-hydroxy-3-[({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; (3aR,7aS)-hexahydro-4H-furo[2,3-b]pyran-3-yl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-
[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; 3-pyridinylmethyl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; 4-pyridinylmethyl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propylcarbamate; l,3-thiazol-5-ylmethyl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; and N-{(2R,3S)-2-hydroxy-3-[({4-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-4- phenylbutyl} -4-[(E)-(hydroxyimino)methyl]-N-isobutylbenzenesulfonamide; or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof. In a second embodiment, the present invention provides a compound of formula (II)
Figure imgf000022_0001
(II) or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, wherin
R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl or heteroarylalkyl; wherein each R is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, formyl, nitro, hydroxy, alkoxy, -ΝH2, -N(H)alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, haloalkyl, hydroxyalkyl and alkoxyalkyl; Ri is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rla)NRaRb or -OC(=O)C(H)(Rla)N(H)C(O)ORa;
Rla is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each Rιa is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaR , -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Ra)SO2NRaR , -N(R )C(=NH)NRaRb, -N(Rb)C(=O)NRaR , -C(=O)NRaR and -C(=O)ORa; R2 is H;
R is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, -alkylSRa, -alkylSORa, -alkylSO2Ra, - alkylNRaR , -alkylN(R )C(=O)ORa, -alkylN(Rb)C(=O)Ra, -alkylN(R )SO2Ra or -alkylN(Rb)SO2NRaRb; wherein each of the cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the cycloalkenylalkyl, hetrocycle moiety of the heterocyclealkyl, heteroaryl moiety of the heteroarylalkyl, aryl moiety of the arylalkyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), - N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS (alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(HXalkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2, -alkylC(=O)alkyl and R3a;
R3a is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, wherein each R3a is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(=O)alkyl,
-N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(O)N(alkyl)2, -C(= )alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyI)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2 and -alkylC(=O)alkyl;
R4 is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl wherein each is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, alkyl, oxo, alkenyl, alkynyl, nitro, cyano, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, nitroalkyl, -OR^, -SRta, -SOR4a, -SO2R4a, -NR4aR4 , -OC(=O)R a, -C(=O)R4a, -C(=O)OR4a,
Figure imgf000023_0001
-N(R4b)C(=O)NR4aR4 , -N(R4b)SO2NR4aR4 , -alkylSRa, -alkylSOR4a, -alkylSO^,, -alkylNR4aR4 ,
Figure imgf000024_0001
-alkylN(R4b)C(=O)R4a, -alkylN(R4b)C(=O)OR4a, -alkylN(R4 )SO2R4a, -alkylN(R4b)C(=O)NR4aR , -alkylN(R4 )SO2NR4aR4b, -N(H)C(=O)alkylN(H)C(=O)OR4a, -N(H)C(=O)alkylNR aR4 , -C(R4b)=NOR4a, -C(NR4aR4b)=NOR4a and -C(R4b)=NOC(=O)alkylNR4aR4b;
R a and R b, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl and heteroalkyl; wherein each ja and R b, at each occurrence, is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, hydroxy, alkoxy, halo, nitro, cyano, formyl, oxo, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)alkyl, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)alkyl, -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, cyanoalkyl, nitroalkyl, formylalkyl and alkoxyalkyl; R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; wherein each R7 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, -ORa, -OalkylC(=O)NRaR , -SRa, -SORa, -SO2Ra, -SO2NRaRb, -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Rar-N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Rb)SO2NRaRb, -N(Rb)C(=NH)NRaR , -N(Rb)C(=O)NRaRb, -C(=O)NRaR , -C(=O)ORa and R7a; R7a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkyϊNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(-O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2; R8 is -C(=O)OR8a or -C(=O)alkylNR8aR8 , R8a and R8b are, at each occurrence, independently selected from the group consisting of alkyl, arylalkyl and heteroarylalkyl; wherein each R8a and R8b is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of alkyl, nitro, hydroxy, alkoxy, amino, formyl, halo, haloalkyl, hydroxyalkyl, alkoxyalky aminoalkyl and formylalkyl; Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle; wherein each Ra and Rb, at each occurrence, is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C θ)NH2,
-alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC θ)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Ro; alternatively, Ra and R , together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkyhSfflb, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl),
-alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Rc; and
Re is aryl, heteroaryl or heterocycle; wherein each Re is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(allyι)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)2, -alkyl-N(H)C(=O)NH2, -alkyl-N(H)C(=O)N(H)(alkyl), -alkyl-N(H)C(=O)N(alkyl)2, -alkyl-C(=O)OH, -alkyl-C(=O)Oalkyl, -alkyl-C(=O)NH2, -alkyl-C(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2. For example, the present invention provides a compound of formula (II) wherein Ri is OH and R2 is H. For example, the present invention provides a compound of formula (II) wherein Ri is OH, R2 is H and R3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra or -alkylNRaRb. For example, the present invention provides a compound of formula (II) wherein Ri is OH, R2 is H, R3 is alkyl or cycloalkyl and is aryl or heteroaryl. For example, the present invention provides a compound of formula (II) wherein Ri is
OH, R2 is H, R3 is alkyl or cycloalkylalkyl and I is phenyl. For example, the present invention provides a compound of formula (II) wherein Rt is OH, R2 is H, R3 is alkyl or cycloalkylalkyl and i is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORia, -NR^ n, and -C(R )=NOR4a; wherein Rta and n, are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (II) wherein Ri is OH, R2 is H, R3 is alkyl or cycloalkylalkyl, i is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -O a, - taRib and -C(R4b)=NOR a, and R7 is alkyl; wherein ιa and n, are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (II) wherein Ri is OH, R is H, R3 is alkyl or cycloalkylalkyl, R is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -NR4aR4b and -C(R4b)=NOR4a, R7 is alkyl and R is phenylmethyl; wherein ta and R-n, are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (II) wherein Ri is OH, R2 is H, R3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, R4 is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR^, -NE ^R^, and -C(R4b):=:NOR a, R is alkyl and R is phenylmethyl; wherein R a and R are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (II) wherein R is OH, R2 is H, R3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, R4 is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR a,
Figure imgf000026_0001
and -C(R4b)=NOR4a, R7 is CI alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5 alkyl and R is phenylmethyl; wherein R4a and ^ are independently selected from the group consisting of hydrogen and alkyl. Exemplary compounds of the present invention of formula (II) include, but not limited to, the following: tert-butyl (lS)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2,2- dimethylpropylcarbamate; benzyl (lS)-3-amino-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-3- oxopropylcarbamate; methyl (lS)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2,2- dimethylpropylcarbamate; 2-pyridinylmethyl (lR)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} amino)carbonyl]-2- methylpropylcarbamate; 2-pyridinylmethyl (IS)- 1 -[( {(1S,2R)-1 -benzyl-2-hydroxyr3-[( {4-[(E»- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- methylpropylcarbamate; benzyl (lS)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- methylpropylcarbamate; benzyl (lS,2R)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- hydroxypropylcarbamate; tert-butyl (1S,2S)-1 -[( {(1 S,2R)-1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- methylbutylcarbamate; benzyl (lS2S)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} amino)carbonyl] -2- methylbutylcarbamate; tert-butyl (lS)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-3- (methylsulfonyl)propylcarbamate; benzyl (lR)-l-[(aminosulfonyl)methyl]-2-({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)-2- oxoethylcarbamate; benzyl (lS)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]ρhenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-3- (methylsulfanyl)propylcarbamate; benzyl (lS)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino3propyl}amino)carbonyl]-3- methylbutylcarbamate; benzyl (lS)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} amino)carbonyl]-2,2- dimethylpropylcarbamate; benzyl (lS)-4-amino-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}arnino)carbonyl]butylcarba mate; benzyl (lS)-2-( {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)~ (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} amino)- 1 -(lH-imidazol-4- ylmethyl)-2-oxoethylcarbamate; benzyl (lS)-2-({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)-l-(lH-indol-3- ylmethyl)-2-oxoethylcarbamate; benzyl (lS,2R)-2-(2-amino-2-oxoethoxy)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[( {4-
[(£)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]propylcarba mate; methyl (3S)-4-({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} amino)-3- {[(benzyloxy)carbonyl]amino}-4-oxobutanoate; 2-pyridinylmethyl (lS,2S)-l-[({(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2 -hydroxypropyl} amino)carbonyl]-2- methylbutylcarbamate; [6-(methoxymethyl)-2-pyridinyl]methyl (1S,2S)- 1 -[( {(1S,2R)- 1 -benzyl-3-
[(cyclopentylmethyl)({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2- hydroxypropyl}amino)carbonyl]-2-methylbutylcarbamate; [6-(methoxymethyl)-2-pyridinyl]methyl (lS)-l-[({(lS,2R)-l-benzyl-3- [(cyclopentylmethyl)({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2- hydroxypropyl} amino)carbonyl]-2,2-dimethylpropylcarbamate; (2S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-( { [(3- fluorobenzyl)amino]acetyl}amino)-3,3-dimethylbutanamide; (2R)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-( { [(3- fluorobenzyl)amino]acetyl}amino)-3,3-dimethylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-({[(3- fluorobenzyl)amino]acetyl}amino)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[({[(5-nitro-3- thienyl)methyl] amino} acetyl)amino]pentanamide; and benzyl (lS)-4-{[amino(imino)methyl]amino}-l-[({(lS,2R)-l-benzyl-2-hydroxy-3- t({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]butylcarba mate; or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof. In a third embodiment, the present invention provides a compound of formula (III)
Figure imgf000029_0001
or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, wherein X is O, S or NH;
R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl or heteroarylalkyl; wherein each R is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, formyl, nitro, hydroxy, alkoxy, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, haloalkyl, hydroxyalkyl and alkoxyalkyl; Ri is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rla)NRaRb or -OC(=O)C(H)(Rla)N(H)C(O)ORa;
Rla is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each Rla is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -ORa, -SRa, -SORa,
-SO2Ra, -SO2NRaRb, -C(=O)Ra, -NRaRb, -N(Rb)C O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Ra)SO2NLRaRb, -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaR and
-C(=O)ORaJ
R2 is H; R3 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra, -alkylNRaRb, -alkylN(Rb)C(=O)ORa, -alkylN(R )C(=O)Ra, -alkylN(Rb)SO2Ra or -alkylN(Rb)SO2NRaRb; wherein each of the cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the cycloalkenylalkyl, hetrocycle moiety of the heterocyclealkyl, heteroaryl moiety of the heteroarylalkyl, aryl moiety of the arylalkyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), - N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2, -alkylC(=O)alkyl and R3a;
R3a is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, wherein each R3a is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl,, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(=O)alkyl,
-N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyI), -C(O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2 and -alkylC(-O)alkyl; i is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl wherein each R4 is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, alkyl, oxo, alkenyl, alkynyl, nitro, cyano, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, nitroalkyl, -OR4a, -SRia, -SO ta, -SO2Rta, -NR4aR4b, -OC(=O)R4a, -C(=O)R4a, -C(=O)OR4a, -C(-O)N 4aR4 , -N(R4b)C(=O)R4a, -N(R4b)C(=O)OR4a, -N(R4b)SO2R4a, -N(R4b)C(=O)NR4aR4b, -N(R4b)SO2NR4aR4b, -alkylSRa, -alkylSORa, -alkylSO2R4a, -alkylNIUa n:, -alkylOC(=O)R4a, -alkylC(=O)R4a, -alkylC(=O)OR4a, -alkylC(=O)NR aR b, -alkylN(R4b)C(=O)R4a, -alkylN(R4b)C(=O)OR4a, -alkylN(R4b)SO2R4a, -alkylN(R4b)C(=O)NR4aR4 , -alkylN(R4b)SO2NR4aR4 , -N(H)C(=O)alkylN(H)C(=O)OR4a, -N(H)C(=O)alkylNR4aR4 , -C(R4b)=NOR4a, -C(NR4aR4b)=NOR4a and -C(R4b)=NOC(=O)alkylNR4aR4 ;
R-ta and n,, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl and heteroalkyl; wherein each R^ and R b, at each occurrence, is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, hydroxy, alkoxy, halo, nitro, cyano, formyl, oxo, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)alkyl, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)alkyl, -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, cyanoalkyl, nitroalkyl, formylalkyl and alkoxyalkyl;
R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; wherein each R7 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, -ORa, -OalkylC(=O)NRaRb, -SRa, -SORa, -SO2Ra, -SO2NRaR , -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(R )C(=O)ORa, -N(Rb)SO2Ra, -N(Rb)SO2NRaR , -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaR , -C(=O)ORa and R7a; R7a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R7a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2; R9 is alkyl, alkenyl, alkynyl, -C(=O)NRaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R9 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb, -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaRb, -N(Rb)SO2NRaRb, -C(=O)Ra, -C(=O)NRaR , -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaR , -C(H)=N(ORa), -C(alkyl)-N(ORa), -C(H)=NNRaR ,
Figure imgf000031_0001
-alkylN(Rb)NRaR , -alkylN(Rb)C(=O)Ra, -alkylN(R )C(=O)ORa, -alkylN(R )C(=O)NRaRb, -alkylN(Rb)SO2NRaRb, -alkylN(Rb)SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaRb and R9a; R9a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R9a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C θ)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(aιkyl)2; Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle; wherein each Ra and Rb, at each occurrence, is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nifroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Re; alternatively, Ra and Rb, together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(-O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and ,; Re is aryl, heteroaryl or heterocycle; wherein each Re is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)2, -alkyl-N(H)C(=O)NH2, -alkyl-N(H)C(=O)N(H)(alkyl), -alkyl-N(H)C(=O)N(alkyl)2, -alkyl-C(=O)OH, -alkyl-C(=O)Oalkyl, -alkyl-C(=O)NH2, -alkyl-C(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2; and n is 1 or 2. For example, the present invention provides a compound of formula (III) wherein Ri is OH and R2 is H. For example, the present invention provides a compound of formula (III) wherein Ri is OH, R2 is H, X is O and R3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra or -alkylNRaRb. For example, the present invention provides a compound of formula (III) wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkyl and j is aryl or heteroaryl. For example, the present invention provides a compound of formula (III) wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl and R4 is phenyl. For example, the present invention provides a compound of formula (III) wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl and R is, phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -O 4a, -NR^ ^ and
-C(R4b)=NOR4a; wherein R a and n, are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (III) wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl, R is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR4a, -NR aR4b and
-C(R4b)=NOR4a, and R7 is alkyl; wherein ιa and R are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (III) wherein R\ is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl, is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -NR^R^, and
-C(R4b)=NOR a, R7 is alkyl and R is phenylmethyl; wherein R^ and R4b are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (III) wherein Ri is OH, R2 is H, X is O, R3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, R4 is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORtø, -N ^R^ and -C(R4b)=NOR4a, and R7 is alkyl and R is phenylmethyl; wherein ia and R^ are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (III) wherein Ri is OH, R2 is H, X is O, R3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, R is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR4a, -NR aR4b and -CQ HJ^NOR^, and R7 is CI alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl and R is phenylmethyl; wherein ia and R b are independently selected from the group consisting of hydrogen and alkyl. Exemplary compounds of the present invention of formula (III) include, but not limited to, the following: (2S)-N- {(1 S,2R)-1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3 - { [2-(methoxymethyl)- 1 ,3 -thiazol-4-yl]methyl} -2-oxoimidazolidin- 1 -yl)-3 -methylbutanamide; (2S)-N- {(1S,2R)-1 -benzyl-2-hydroxy-3-[( {4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3,3-dimethyl-2- {3-[(l - methyl-lH-benzimidazol-2-yl)methyl]-2-oxoimidazolidin-l-yl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(5-nitro-3- thienyl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(4- quinolinylmethyl)- 1 -imidazolidinyl]butanamide; (2S)-2-(3- { [2-(acetylamino)- 1 ,3 -thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)-N- {(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({2- [(dimethylamino)methyl] -1,3 -thiazol-4-yl} methyl)-2-oxo- 1 -imidazolidinyl] -3 - methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(tetrahydro-2-furanylmethyl)amino]propyl}-3- methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[2-(dimethylamino)ethyl]({4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N- {(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(2-furylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino] -2 -hydroxypropyl} -3 -methyl-2- { 3 - [(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(2-pyridinylmethyl)amino]propyl}-3-methyl-2- {3- [(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-{3-[(2,5-dimethyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[3-(3- nifrobenzyl)-2-oxo- 1 -imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(3- pyridinylmethyl)- 1 -imidazolidinyl]butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(l-methyl- lH-benzimidazol-2-yl)methyl]-2-oxo- 1 -imidazolidinyl}pentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(2-methoxyethyl)amino]propyl} -3-methyl-2- {3-[(2- methyl- 1 ,3 -thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -2-(3- { [2- (methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} -2-oxo- l-imidazolidinyl)-3-methylbutanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(3- pyridinylmethyl)- 1 -imidazolidinyl]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(3- pyridinylmethyl)- 1 -imidazolidinyfjpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(4- pyridinylmethyl)- 1 -imidazolidinyl]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(4- pyridinylmethyl)- 1 -imidazolidinyl]pentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)(2-hydroxypropyl)amino]propyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(4- quinolinylmethyl)- 1 -imidazolidinyl]pentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)[2-(2-thienyl)ethyl]amino}propyl)-3-methyl-2-{3- [(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl} pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(4- quinolinylmethyl)- 1 -imidazolidinyl]pentanamide; (2S,3S)-2-(3- { [2-(acetylamino)- 1 ,3-thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)-N- {(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methylpentanamide; (2S,3S)-2-(3- { [2-(acetylamino)- 1 ,3 -thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)-N-
{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S,3S)-2-[3-(lH-benzimidazol-5-ylmethyl)-2-oxo-l-imidazolidinyl]-N-{(lS,2R)-l- benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)[(lS)-l-(hydroxymethyl)-2- methylpropyl] amino } propyl)-3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyl}butanamide; (2S)-N((1S,2R)-1 -benzyl-2-hydroxy-3- {({4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl) [(IR)- 1 -(hydroxymethyl)-2- methylpropyl] amino } propyl)-3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyl}butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(4- quinolinylmethyl)- 1 -imidazolidinyl]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(4-methyl- 3-pyridinyl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(6-methyl- 2-pyridinyl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(2- pyridinylmethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3 - { [6-(methoxymethyl)- 2-pyridinyl]methyl}-2-oxo-l-imidazolidinyl)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-(3-{[6-
(methoxymethyl)-2-pyridinyl]methyl}-2-oxo-l-imidazolidinyl)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(2- quinolinylmethyl)- 1 -imidazolidinyl]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-(3-cyanobenzyl)-2- oxo- 1 -imidazolidinyl] -3 -methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-(2-oxo-3-{[2- (trifluoromethyl)-l,3-thiazol-4-yl]methyl}-l-imidazolidinyl)pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(l- methyl-lH-benzimidazol-2-yl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(8- quinolinylmethyl)- 1 -imidazolidinyl]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(8- quinolinylmethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-{3-[(2-isopropyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylpentanamide; (2S,3S)-N- {(1S,2R)-1 -benzyl-3-[(cyclopentylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-{3-[(2-isopropyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylpentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-{3-[(2-isopropyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylbutanamide; (2S)-N {(1S,2R)~ 1 -benzyl-3-[(cyclopentylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-{3-[(2-isopropyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-(3-{[2-(methoxymethyl)- l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]ρhenyl}sulfonyl)amino]-2-hydroxypropyl}-2-(3-{[2-
(methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({2-[N- hydroxy ethanimidoyl] -4-pyridinyl} methyl)-2-oxo- 1 -imidazolidinyl] -3 -methylpentanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(7- quinolinylmethyl)- 1 -imidazolidinyl jpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(6- quinolinylmethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)~ (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2-(2-oxo-3- {[2- (2-pyridinyl)- 1 ,3-thiazol-4-yl]methyl} - 1 -imidazolidinyl)pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(7- quinolinylmethyl)- 1 -imidazolidinyl]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentyhnethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(6- quinolinylmethyl)- 1 -imidazolidinyl]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({2-[(E)-
(dimethylhydrazono)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]-3- methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(neopentyl)amino]propyl}-3-methyl-2-{3-[(l- methyl- lH-benzimidazol-2-yl)methyl]-2-oxo- 1 -imidazolidinyljpentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)[4-(2-pyridinyl)benzyl]amino}propyl)-3-methyl-2- {3-[(2-methyl-l,3-thiazol-4-yl)methyl3-2-oxo-l-imidazolidinyl}butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -2-[3-( {2-[(lE)-N- hydroxyethanimidoyl]-4-pyridinyl}methyl)-2-oxo-l-imidazolidinyl]-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({6-[(lE)-N- hydroxyethanimidoyl] -2-pyridinyl} methyl)-2-oxo- 1 -imidazolidinyl] -3 -methylpentanamide; (2S,3S)-2-{3-[(6-{[acetyl(methyl)amino]methyl}-2-pyridinyl)methyl]-2-oxo-l- imidazolidinyl}-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-(3-{[2-(l- methylhydrazino)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-(2-oxo-3-{[2- (3-pyridinyl)- 1 ,3-thiazol-4-yl]methyl} - 1 -imidazolidinyl)pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {2-oxo-3-[(6- pyridin-2-yl-2-pyridinyl)methyl]-l-imidazolidinyl}pentanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)~ (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(2-methyl- 4-quinolinyl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(4-methyl- 2-quinolinyl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2- {3-[(6-isopropyl-2- pyridinyl)methyl]-2-oxo- 1 -imidazolidinyl} -3 -methylpentanamide; (2S,3S)-N- {(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -3-methyl-2- {3-[(6- methyl-2-pyridinyl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(4- methyl-3 -pyridinyl)methyl] -2-oxo- 1 -imidazolidinyl} pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3 - { [4-(methoxymethyl)- 2-pyridinyl]methyl} -2-oxo- 1 -imidazolidinyl)-3-methylpentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-(2-oxo-3- {[2-(3-pyridinyl)-l,3-thiazol-4-yl]methyl}-l-imidazolidinyl)butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-[2-oxo-3- (4-quinolinylmethyl)- 1 -imidazolidinyl]butanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-3-[(cyclopentylmethyl)( {4-[(E (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(3- pyridinylmethyl)- 1 -imidazolidinyljpentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-[2-oxo-3- (3-pyridinylmethyl)- 1 -imidazolidinyljbutanamide; (2S,3S)-2- {3 -[(2- { [acetyl(methyl)amino]methyl} - 1 ,3-thiazol-4-yI)methyl] -2-oxo- 1 - imidazolidinyl} -N- {(1S,2R)-1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3 -methylpentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-{3-[(2- methyl-4-quinolinyl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-[2-oxo-3- (6-quinolinylmethyl)- 1 -imidazolidinyljbutanamide; (25)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-[2-oxo-3- (7-quinolinylmethyl)- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-(2-oxo-3- { [2-(2-pyridinyl)- 1 ,3-thiazol-4-yl]methyl} - 1 -imidazolidinyl)butanamide; {4-[(3-{(lS,2S)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- methylbutyl}-2-oxo-l-imidazolidinyl)methyl]-l,3-thiazol-2-yl}methyl acetate; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3- { [6-(methoxymethyl)- 2-pyridinyl]methyl} -2-oxo- 1 -imidazolidinyl)-3 ,3 -dimethylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-(3-{[2-(methoxymethyl)- l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-3,3-dimethylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{2-oxo-3-[3-(3- pyridinyl)benzyl]- 1 -imidazolidinyl}pentanamide; (2S)-2-[3-({2-[(lS)-l-(acetylamino)ethyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l- imidazolidinyl]-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3 ,3 -dimethylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-(3-{[2-(6- methyl-3-pyridinyl)- 1 ,3 -thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-(2-oxo-3- { [2-(4-pyridinyl)- 1 ,3-thiazol-4-yl]methyl} - 1 -imidazolidinyljbutanamide; (2S)-N- {(1S,2R)-1 -benzyl-2-hydroxy-3-[( {4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-(2-oxo-3- { [2-(2-thienyl)- 1 ,3-thiazol-4-yl]methyl} - 1 -imidazolidinyl)butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl- 3-pyridinyl)methyl]-2-oxo- 1 -imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(6-methyl- 3-pyridinyl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; ethyl {6-[(3-{(lS,2S)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} amino)carbonyl]-2- methylbutyl}-2-oxo-l-imidazolidinyl)methyl]-2-pyridinyl}methyl(methyl)carbamate; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-(3-{[6-(hydroxymethyl)- 2-pyridinyl]methyl} -2-oxo- 1 -imidazolidinyl)-3 ,3 -dimethylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{2-oxo-3-[3- (1 ,3-thiazol-2-yl)benzyl]- 1 -imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{2-oxo-3-[3-(2- pyridinyl)benzyl]-l-imidazolidinyl}pentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-(3-{[2-(5- methyl-3-isoxazolyl)- 1 ,3 -thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-{3-[(3- methyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S,35)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-{3-[(2,4-dimethyl-3- pyridinyl)methyl]-2-oxo-l-imidazolidinyl}-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-{3-[3-(3-furyl)benzyl]-2- oxo-l-imidazolidinyl}-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {2-oxo-3-[3-(4- pyrimidinyl)benzyl]-l-imidazolidinyl}pentanamide; (2S,3S)-N- {(1S,2R)-1 -benzyl-2-hydroxy-3-[( {4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2- {3 - [(6-methoxy-3 - pyridinyl)methyl] -2-oxo- 1 -imidazolidinyl} -3-methylpentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-(2-oxo-3- { [2-(2-pyrazinyl)- 1 ,3-thiazol-4-yl]methyl} - 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3 - { [6-(l -hydroxy- 1 - methylethyl)-2-pyridinyl]methyl}-2-oxo-l-imidazolidinyl)-3,3-dimethylbutanamide; (2S,3S)-N-{(1S,2R)- 1 -benzyl-3-[(cyclopentylmethyl)( {4-[(E)- (hydrox)άmino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2- methyl-3-pyridinyl)methyl]-2-oxo- 1 -imidazolidinyl}pentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3,3-dimethyl-2- {3-[(6- methyl-3-pyridinyl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-[2-oxo-3- (4-pyridazinylmethyl)- 1 -imidazolidinyljbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(4- pyridazinylmethyl)- 1 -imidazolidinyl]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(3- pyridazinylmethyl)- 1 -imidazolidinyl]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(3-methyl- 3H-imidazo[4,5-b]pyridin-2-yl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxoimidazolidin- 1 -yl} butanamide; (2S)-N- {(1 S,2R)-l-benzyl-2-hydroxy-3-[( {4-[(E (hydroxyimmo)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3 -methyl-2-[3 -( {2- [(methylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxoimidazolidin-l-yl]butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(pyrrolidin-2-ylmethyl)amino]propyl}-3-methyl-2- {3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxoimidazolidin-l-yl}butanamide; (2S)-2-[3-(3-aminobenzyl)-2-oxoimidazolidin-l -yl]-N- {(1 S,2R)- 1 -benzyl-2- hydroxy-3-[({4-[(E)-(hydroxyiinino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3- methylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(l-oxido-3- pyridinyl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(l- oxidopyridin-4-yl)methyl]-2-oxoimidazolidin-l-yl}pentanamide; (2S,3S)-2-(3-{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}-2-oxoimidazolidin-l-yl)-N- {(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S,3S)-2-(3-{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N- {(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)-
(hydroxyimino)metlιyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methylpentanamide; (2S,3S)-2-(3-{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N-
{(1 S,2R)- 1 -benzyl-3-[(cyclopentylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hyαLiOxypropyl}-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-[3 -( {2- [N- hydroxyethanimidoyl]pyridin-4-yl}methyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl]-3- methylpentanamide; (2R,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-[3-({2- [(isopropylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]-3- methylpentanamide; (2S,3S)-N- {(1 S,2R)-1 -benzyl-3-[(cyclopentylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-[3-({2- [(isopropylamino)methyl] -1,3 -thiazol-4-yl} methyl)-2-oxo- 1 -imidazolidinyl] -3 - methylpentanamide; (2S,3S)-2-(3-{3-[amino(hydroxyimino)methyl]benzyl}-2-oxo-l-imidazolidinyl)-N- {(1 S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2- {3-[3- (hydroxymethyl)benzyl]-2-oxo-l-imidazolidinyl}-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({6- [(hydroxyimino)methyl]-2-pyridinyl}methyl)-2-oxo-l-imidazolidinyl]-2,3- dimethylpentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3- { [6-( 1 -hydroxyethyl)- 2-pyridinyl]methyl}-2-oxo-l-imidazolidinyl)-3,3-dimethylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2-isopropyl-l,3-thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyl} -3 -methylbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl] amino } propyl)-3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] - 2-oxo-l-imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propyl)-3 -methyl-2- [2-oxo-3 -(3 -thienylmethyl)- 1 - imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2-ethyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4-yl]methyl}- 2-oxo- l-imidazolidinyl)-3-methylbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyρhenyl)sulfonyl]amino}propyl)-3-methyl-2-[2-oxo-3-(l,3-thiazol-2-ylmethyl)-l- imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(3,5-dimethyl-l-phenyl-lH-pyrazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(5-ethyl-2-phenyl-l,3-thiazol-4-yl)methyl]-2- oxo- 1 -imidazolidinyl} -3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(5-ethyl-2-methyl-l,3-thiazol-4-yl)methyl]-2- oxo- 1 -imidazolidinyl} -3 -methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2,5-dimethyl-l,3-thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyl} -3-methylbutanamide; (2S)-N-((1S,2R)- 1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl] amino } propyl)-3 -methyl-2- {3 - [(5 -nitro-3 -thienyl)methyl] -2-oxo- 1 - imidazolidinyljbutanamide; (2S)-2-[3-(l-benzotlιien-3-ylmethyl)-2-oxo-l-imidazolidinyl]-N-((lS,2R)-l-benzyl-2- hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3-methylbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(l-methyl-lH-benzimidazol-2- yl)methyl] -2-oxo- 1 -imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(l-methyl-lH-indol-2-yl)methyl]-2- oxo- 1 -imidazolidinyljbutanamide; (2S)-N-((1S,2R)- 1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-[2-oxo-3-(2-quinolinylmethyl)-l- imidazolidinyl]butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino }propyl)-2- {3-[(2-cyclopropyl- 1 ,3-thiazol-4-yl)methyl]-2- oxo- 1 -imidazolidinyl} -3 -methylbutanamide; (2S)-2- {3-[(2-acetyl-l ,3-thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyl} -N-((1S,2R)- 1 - benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2-isobutyryl-l,3-thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyl} -3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2-butyryl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}-3-methylbutanamide; (2S)-N-((1 S,2R)- 1 -benzyl-2-hydroxy-3 - {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(5-nitro-2-thienyl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(2-nitro-l,3-thiazol-4-yl)methyl]-2- oxo-l-imidazolidinyl}butanamide; (2S)-2-(3-{[2-(azidomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N- (( 1 S,2R)- 1 -benzyl-2-hydroxy-3 - {isobutyl[(4-methoxyphenyl)sulfonyl] amino } propyl)-3 - methylbutanamide; (2S)-N-((1S,2R)- 1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{2-oxo-3-[(2-propionyl-l,3-tlιiazol-4- yl)methyl] - 1 -imidazolidinyl} butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3,3-dimethyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo- 1 -imidazolidinyljbutanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo- 1 -imidazolidinyl}pentanamide; (2S)-N1-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanediamide; (4-{[3-((lS)-l-{[((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)amino]carbonyl}-2-methylpropyl)-2-oxo-l- imidazolidinyl]methyl}-l,3-thiazol-2-yl)methyl acetate; (2S)-N1-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}pentanediamide; (2S)-2-[3-(l-benzofuran-2-ylmethyl)-2-oxo-l-imidazolidinyl]-N-((lS,2R)-l-benzyl-2- hydroxy-3 - {isobutyl[(4-methoxyphenyl)sulfonyl] amino } propyl)-3 -methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propyl)-3 -methyl-2- [2-oxo-3 -(3 -quinolinylmethyl)- 1 - imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(4-methoxy-5-nitro-3-thienyl)methyl]-2-oxo- 1 -imidazolidinyl} -3 -methylbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-[3-({2-[(methylsulfanyl)methyl]-l,3- thiazol-4-yl} methyl)-2-oxo- 1 -imidazolidinyl]butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-(3-{[2-(cyanomethyl)-l,3-thiazol-4-yl]methyl}-2- oxo- 1 -imidazolidinyl)-3-methylbutanamide; (2S)-2-(3-{[2-(acetylamino)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N- ((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(8-hydroxy-2-quinolinyl)methyl]-2-oxo-l- imidazolidinyl}-3-methylbutanamide; (2S,3S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(l-methyl-lH-benzimidazol-2- yl)methyl] -2-oxo- 1 -imidazolidinyl} pentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(4-methoxy-2-quinolinyl)methyl]-2-oxo-l- imidazolidinyl}-3-methylbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-[2-oxo-3-(2-quinoxalmylmethyl)-l- imidazolidinyljbutanamide; (2S)-N1-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-N4-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl] -2-oxo- 1 -imidazolidinyl}butanediamide; (2S)-N1-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-N4-ethyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo-l-imidazolidinyl}butanediamide; (2S,3S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-l- imidazolidinyl]pentanamide; (2S,3S)-2-[3-(lH-benzimidazol-5-ylmethyl)-2-oxo-l-imidazolidinyl]-N-((lS,2R)-l- benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylpentanamide; (2S)-N-((lS,2R)-l-benzyl-3-{(cyclopentylmethyl)[(4- methoxyphenyl)sulfonyl]amino}-2-hydroxypropyl)-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4- yl]methyl}-2-oxo-l-imidazolidinyl)-3-methylbutanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-[2-oxo-3-(2-quinolinylmethyl)-l- imidazolidinyl]pentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-3-{(cyclopentylmethyl)[(4- methoxyphenyl)sulfonyl]amino}-2-hydroxypropyl)-3-methyl-2-{3-[(l-methyl-lH- benzimidazol-2-yl)methyl]-2-oxo- 1 -imidazolidinyl}pentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4-yl]methyl}- 2-oxo-l-imidazolidinyl)-3-methylpentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino }propyl)-2- [3 -(3 -cyanobenzyl)-2-oxo- 1 -imidazolidinyl] -3 - methylpentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3,3-dimethyl-2-{3-[(l-methyl-lH-benzimidazol-2- yl)methyl]-2-oxo- 1 -imidazolidinyljbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]aminoJpropyl)-3-(formylamino)-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl] -2-oxo- 1 -imidazolidinyljpropanamide; (2S)-3-[(aminocarbonyl)amino]-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]aminoJpropyl)-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljpropanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]aminoJpropyl)-2-(3-{[6-(methoxymethyl)-2-pyridinyl]methylJ-2- oxo- 1 -imidazolidinyl)-3 -methylpentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propyl)-2- [3 -( {2- [( lE)-N-hydroxy ethanimidoyl] -4- pyridinyl}methyl)-2-oxo-l-imidazolidinyl]-3-methylpentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-(2-oxo-3-{[2-(2-pyridinyl)-l,3-thiazol- 4-yl]methyl} - 1 -imidazolidinyl)pentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-(2-oxo-3-{[2-(3-pyridinyl)-l,3-thiazol- 4-yl]methyl} - 1 -imidazolidinyl)pentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino}propyl)-2-(3 - { [2-(methoxymethyl)- 1 ,3 -thiazol-4-yl]methyl} - 2-oxo-l-imidazolidinyl)-3,3-dimethylbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl] amino }propyl)-3 ,3 -dimethyl-2-(2-oxo-3 - { [2-(3-pyridinyl)- 1,3- thiazol-4-yl]methyl} - 1 -imidazolidinyljbutanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-(3-{[2-(2-methyl-l,3-thiazol-4yl)-l,3- thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)pentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-(3-{[2-(2-ethyl-4-pyridinyl)-l,3-thiazol-4- yl]methyl} -2-oxo- 1 -imidazolidinyl)-3 -methylpentanamide; (2S,3S)-N-((1S,2R)- 1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-(3-{[2-(6-methyl-3-pyridinyl)-l,3- thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)pentanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-3 ,3 -dimethyl-2- {3 - [(3 -methyl-3H-imidazo [4,5- b]pyridin-2-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-3 -methyl-2- {3 - [(3 -methyl-3H-imidazo [4,5- b]pyridin-2-yl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-3-{(cyclopentylmethyl)[(4- methoxyphenyl)sulfonyl]amino}-2-hydroxypropyl)-3-methyl-2-(2-oxo-3-{[2-(3-pyridinyl)- 1 ,3-thiazol-4-yl]methyl} - 1 -imidazolidinyl)pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- methoxyphenyl)sulfonyl](neopentyl)amino]propyl}-3-methyl-2-(2-oxo-3-{[2-(3-pyridinyl)- 1 ,3-thiazol-4-yl]methyl} - 1 -imidazolidinyl)pentanamide; (2S)-2-(3 - { [2-(aminomethyl)- 1 ,3-thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)-N-
(( 1 S,2R)- 1 -benzyl-2-hydroxy-3 - {isobutyl [(4-methoxyphenyl)sulfonyl] amino } propy l)-3 - methylbutanamide; (2S)-2-[3-({2-[(acetylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l- imidazolidinyl]-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-3 -methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-2-(3 - { [2-(hydroxymethyl)- 1 ,3-thiazol-4-yl]methyl} - 2-oxo-l-imidazolidinyl)-3-methylbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-2- [3 -( {2- [(dimethylamino)methyl]- 1 ,3 -tlιiazol-4- yl}methyl)-2-oxo-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(2- {[(methylsulfonyl)amino]methyl}-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl} butanamide; (26)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-[3-({2-[(hydroxyimino)methyl]-l,3-thiazol-4- yl}methyl)-2-oxo-l-imidazolidinyl]-3-methylbutanamide; methyl (4-{[3-((lS)-l-{[((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)amino]carbonyl}-2-methylpropyl)-2-oxo-l- imidazolidinyl]methyl}-l,3-thiazol-2-yl)methylcarbamate; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-3 -methyl-2- [3 -( {2- [(methylsulfony l)methyl]- 1 ,3 - thiazol-4-yl} methyl)-2-oxo- 1 -imidazolidinyl]butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-[3-({2-[(diethylamino)methyl]-l,3-thiazol-4- yl} methyl)-2-oxo- 1 -imidazolidinyl] -3 -methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[2-(isopropylamino)-2-oxoethyl]-2-oxo-l- imidazolidinyl}-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino }propyl)-3 -methyl-2- [3 -( {2- [(methylamino)methyl] -1,3- thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-[3-({2-[N-hydroxyethanimidoyl]-l,3-thiazol-4- yl}methyl)-2-oxo- 1 -imidazolidinyl]-3 -methylbutanamide; (2S,3S)-2-(3-{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N- ((lS,2R)-l-benzyl-3-{(cyclopentylmethyl)[(4-methoxyphenyl)sulfonyl]amino}-2- hydroxypropyl)-3-methylpentanamide; (2S,3S)-2-(3-{3-[amino(hydroxyimino)methyl]benzyl}-2-oxo-l-imidazolidinyl)-N- ((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylpentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-4-hydroxy-2-{3-[(l-methyl-lH-benzimidazol-2- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl} -3-methyl-2- {3-[(2-methyl-l ,3-thiazol-4- yl)methyl]-2-oxo- 1 -imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl} butanamide; (2S)-N- {(1R,2R)- 1 -benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-2-{3-[(2-isopropyl-l,3-thiazol-4- yl)methyl] -2-oxo- 1 -imidazolidinyl} -3 -methylbutanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2- {3-[(2-isopropyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo-l -imidazolidinyl} -3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{3-[(2-isopropyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-2-{3-[(2-ethyl-l,3-thiazol-4-yl)methyl]-2- oxo- 1 -imidazolidinyl} -3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{3-[(2-ethyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3- methylbutanamide; (2S)-N- {(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l -benzyl-2- hydroxypropyl} -2- {3 -[(2-ethyl- 1 ,3-thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl} -3 - methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-hydroxyphenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl} -2- {3 -[(2-ethyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyl} -3- methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4- yl]methyl}-2-oxo-l-imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2-(3 - { [2-(methoxymethyl)- 1 ,3 -thiazol-4-yl]methyl} -2-oxo- 1 - imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l- imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-hydroxyphenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl}-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l- imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3-{[(l-methyl-lH-imidazol-4- yl)sulfonyl]amino}phenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3,5-dichloro-4- hydroxyphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(5-nitro-3-thienyl)methyl]- 2-oxo- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-hydroxy-3-[(3- pyridinylsulfonyl)amino]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(2- methyl-l,3-tlιiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-hydroxy-3- [(methylsulfonyl)amino]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-2-{3-[(2-cyclopropyl-l,3-thiazol-4- yl)methyl] -2-oxo- 1 -imidazolidinyl} -3 -methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{3-[(2-cyclopropyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{3-[(2-cyclopropyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-ethyl-4-hydroxyphenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3,5-dichloro-2- hydroxyphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl({4- [(methylsulfonyl)amino]phenyl}sulfonyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(5-fluoro-4-hydroxy-2- methylphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(5-chloro-4-hydroxy-2- methylphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl} -3-methyl-2- {3-[(2-methyl- 1,3- thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-chloro-4-hydroxy-5- methylphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- {[(methylamino)sulfonyl]amino}phenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3- [(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; ethyl 2-hydroxy-5- { [ {(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2- {3-[(2-methyl-l ,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanoyl)amino]-4- phenylbutyl}(isobutyl)amino]sulfonyl}phenylcarbamate; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- isopropylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl] -2-oxo- 1 -imidazolidinyl} butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(l-methyl-lH- benzimidazol-2-yl)methyl]-2-oxo-l-imidazolidinyl} butanamide; (26)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3,5- dimethylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(5-nitro-3-thienyl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-nitro-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(4-amino-3-hydroxyphenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; {4-[(3-{(lS)-l-[({(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l- benzyl-2-hydroxypropyl} amino)carbonyl] -2-methylpropyl} -2-oxo- 1 -imidazolidinyl)methylj- l,3-thiazol-2-yl}methyl acetate; (2S)-N- {(lS,2R)-l-benzyl-2-hydroxy-3-[ {[4-hydroxy-3- (methylamino)phenyl] sulfonyl} (isobutyl)amino]propyl} -3 -methyl-2- {3 -[(2-methyl- 1,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[{[3-(dimethylamino)-4- hydroxyphenyl]sulfonyl}(isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-{[(ethylamino)carbonyl]amino}-4- hydroxyphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyljbutanamide; methyl 2-hydroxy-5-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl J butanoyl)amino] -4- phenylbutylJ(isobutyl)amino]sulfonylJphenylcarbamate; benzyl 2-hydroxy-5-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanoyl)amino]-4- phenylbutylJ(isobutyl)amino]sulfonylJphenylcarbamate; (2S)-N-{(lS,2R)-3-[[(l-acetyl-2,3-dihydro-lH-indol-5-yl)sulfonyl](isobutyl)amino]- l-benzyl-2-hydroxypropylJ -3-methyl-2- {3-[(2-methyl-l ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(2-chloro-4-hydroxy-5- methylphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[[(3-acetyl-4-hydroxyphenyl)sulfonyl](isoburyl)amino]-l-benzyl- 2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[[(2-amino-l,3-thiazol-5-yl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(3-quinolinylmethyl)- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(5-nitro-3-thienyl)methyl]-2- oxo- 1 -imidazolidinyl} butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -3 -methyl-2- [2-oxo-3 -(4-quinoliny Imethyl)- 1 -imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[{[4-(2- hydroxyethyl)phenyl]sulfonyl}(isobutyl)aminoJpropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-2-(3 - { [2-(acetylamino)- 1 ,3 -thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)-N- {(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-cyano-4-hydroxyphenyl)sulfonyl](isobutyl)aminoj- 2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S,3S)-N-{(lS,2R)-3-[[(3-aminor4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-
2-hydroxypropyl}-3-methyl-2-{3-[(l-methyl-lH-benzimidazol-2-yl)methyl]-2-oxo-l- imidazolidinyl}pentanamide; (2S3S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl} -3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)- 1 -imidazolidinyljpentanamide; (2S3S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-
2-hydroxypropyl}-2-[3-(lH-benzimidazol-5-ylmethyl)-2-oxo-l-imidazolidinyl]-3- methylpentanamide; (2S5S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(2-quinolinylmethyl)-l-imidazolidinyl]pentanamide; (2S)-N- {(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l -benzyl-2- hydroxypropyl}-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-l,3-thiazol-4-yl]methyl}-l- imidazolidinyl)butanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-l,3-thiazol-4-yl]methyl}-l- imidazolidinyl)butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2-(3- { [2-(methoxymethyl)- 1 ,3 -thiazol-4-yl]methyl} -2-oxo- 1 - imidazolidinyl)-3,3-dimethylbutanamide; (2S3S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxyproρyl}-3-methyl-2-(3-{[2-(2-methyl-l,3-thiazol-4-yl)-l,3-thiazol-4-yl]methyl}-2- oxo- 1 -imidazolidinyl)pentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyljphenyl} sulfonyl)(neopentyl)amino]propyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[{[4-((E)-{[(3- aminopropanoyl)oxy]imino}methyl)phenyl]sulfonyl}(isobutyl)amino]-l-benzyl-2- hydroxypropyl} -3 -methyl-2- {3 - [(2-methyl- 1 ,3 -fhiazol-4-yι)methyl] -2-oxo- 1 - imidazolidinyl} butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(3- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(4-chlorophenyl)sulfonyl](isobutyl)aminoj-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(4-fluorophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3,4-dibromophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N- {(1S,2R)-1 -benzyl-3-[[(l ,2-dimethyl- lH-imidazol-4- yl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(l-methyl-lH-imidazol-4- yl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(4-bromo-5-chloro-2- pyridinyl)sulfonyl](isobutyl)aminoJ-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol- 4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(4-cyanophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl} -3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-fluorophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(4-bromophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl } -3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyl J butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-chloro-4-fluorophenyl)sulfonylj(isobutyl)amino]-2- hydiOxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3,4-dimethoxyphenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl} -3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3,4-dichlorophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[[(4-acetylphenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropylj -3-methyl-2- {3-[(2-methyl-l ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(2,4,6- trichlorophenyl)sulfonyl]aminoJpropyl)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(2-cyanophenyl)sulfonylj(isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-cyanophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(2,5-dichloro-3-thienyl)sulfonyl](isobutyl)aminoj-2- hydroxypropyl J-3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl(2-thienylsulfonyl)amino]propylJ-3- methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methylj-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(2,4-dichlorophenyl)sulfonylj(isobutyl)amino]-2- hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinylj butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(2,3-dichlorophenyl)sulfonyl](isobutyl)aminoj-2- hydroxypropylj -3-methyl-2- {3-[(2 -methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo-l - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3,5-dimethyl-4-isoxazolyl)sulfonyl](isobutyl)amino]- 2-hydroxypropylJ -3-methyl-2- {3-[(2 -methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo-l - imidazolidinyljbutanamide; (2S)-N-(( 1 S,2R)- 1 -benzyl-2-hydroxy-3 - {isobutyl[(2-methoxy-4- methylphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2- oxo- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[{[4-(acetylamino)-3-chlorophenyl]sulfonyl}(isobutyl)aminoj-l- benzyl-2-hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; 2-hydroxy-5-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinylJbutanoyl)amino]-4- phenylbutylj (isobutyl)aminojsulfonylJbenzoic acid; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-fluoro-4-hydroxyρhenyl)sulfonyl](isobutyl)amino]-
2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl(5- isoquinolinylsulfonyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2- oxo-l-imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(3,4,5- trimethoxyphenyl)sulfonyl] amino } propy l)-3 -methyl-2- {3 - [(2-methyl- 1 , 3 -thiazol-4- yl)methyl]-2-oxo-l-imidazolidinylJbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-chloro-4-methylphenyl)sulfonyl](isobutyl)amino]-2- hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[{[2-chloro-5- (trifluoromethyl)phenyl]sulfonyl}(isobutyl)amino]-2-hyαLxOxypropyl}-3-methyl-2-{3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[{[2-chloro-4-
(trifluoromethyl)phenyl]sulfonyl}(isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinylJbutanamide; 4-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo-l-imidazolidinyl}butanoyl)amino]-4-phenylbutyl}(isobutyl)amino]sulfonyl}benzoic acid; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl(phenylsulfonyl)amino]propylJ-3- methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinylJbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(5-bromo-2-methoxyρhenyl)sulfonyl](isobutyl)aminoj- 2-hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(2-oxo-2,3-dihydro-l,3-benzoxazol- 6-yl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-((1S,2R)- 1 -benzyl-2-hydroxy-3- {isobutyl[(4- vinylphenyl)sulfonyl] amino } propy l)-3 -methyl-2- { 3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2- oxo- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(2,3-dihydro-l-benzofuran-5- ylsulfonyl)(isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[ {[4-(l - hydroxyethyl)phenyl]sulfonylJ(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methylJ-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[(l,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-l-benzyl-2- hydroxypropyl J -3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[(l-benzofuran-5-ylsulfonyl)(isobutyl)amino]-l-benzyl-2- hydroxypropylj -3-methyl-2- {3-[(2-methyl-l ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl(3-pyridinylsulfonyl)amino]propyl}- 31-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinylJbutanamide; (2S)-N-{(lS,2R)-3-[{[2-(acetylamino)-4-methyH,3-thiazol-5- yl]sulfonylJ(isobutyl)amino]-l-benzyl-2-hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl} butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(2-methyl-2,3-dihydro-l- benzofuran-5-yl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo- 1 -imidazolidinyl} butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(5-{(Z)-[(benzyloxy)imino]methyl}-2- furyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; methyl 3-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl] -2-oxo- 1 -imidazolidinyl} butanoyl)amino] -4- phenylbutyl}(isobutyl)amino]sulfonyl}benzoate; (2S)-N-{(lS,2R)-3-[[(3-acetylphenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -3-methyl-2- {3-[(2 -methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(l-oxido-4- pyridinyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(2-methyl-l,3-tlιiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(3- hydroxyphenyl)sulfonyl] (isobutyl)aminojpropyl} -3 -methyl-2- {3 -[(2-methyl- 1 ,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(5-bromo-2-hydroxyphenyl)sulfonyl](isobutyl)amino]- 2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl} butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[{[4-(l,2- dihydroxy ethyl)phenyl] sulfonyl} (isobutyl)amino] -2-hydroxypropyl} -3 -methyl-2- {3 - [(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(4-formylphenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl J -3-methyl-2- {3-[(2 -methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyl J butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[{[4- (hydroxymethyl)phenyl]sulfonyl}(isobutyl)amino]propylJ-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[{[4-(formylamino)phenyl]sulfonylJ(isobutyl)amino]-2- hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl J -2-(3 - { [2-(hydroxymethyl)- 1 ,3-thiazol-4-yl]methylJ -2-oxo- 1 - imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[{[3-(acetylamino)-4-hydroxyphenyl]sulfonyl}(isobutyl)amino]-l- benzyl-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; tert-butyl 2-(2-hydroxy-5-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanoyl)amino]-4- phenylbutylj (isobutyl)aminoj sulfonyl} anilino)-2-oxoethylcarbamate; (2S)-N-{(lS,2R)-l-benzyl-3-[{[3-(formylamino)-4- hydroxyphenyl]sulfonyl}(isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-hydroxy-3- [(phenylacetyl)amino]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl}butanarnide; tert-butyl 3-(2-hydroxy-5-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanoyl)amino]-4- phenylbutyl} (isobutyl)amino] sulfonyl} anilino)-3-oxopropylcarbamate; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl({4- [(methoxyimino)methyl]phenyl} sulfonyl)amino Jpropyl} -3 -methyl-2- {3 - [(2-methyl- 1,3- thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(2,3-dihydro-lH-indol-5-ylsulfonyl)(isobutyl)aminoj-2- hydroxypropyl} -3-methyl-2- {3-[(2-methyl-l ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[[(2-amino-4-methyl-l,3-thiazol-5-yl)sulfonyl](isobutyl)amino]-l- benzyl-2-hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[({3-[(3-aminopropanoyl)amino]-4- hydroxyphenylJsulfonyl)(isobutyl)amino]-l-benzyl-2-hydroxypropyl}-3-methyl-2-{3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinylJbutanamide; tert-butyl 2-(3-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3-thiazol- 4-yl)methyl]-2-oxo-l-imidazolidinyl}butanoyl)amino]-4- phenylbutylj (isobutyl)amino] sulfonyl J anilino)-2-oxoethylcarbamate; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[{[3- (hydroxymethyl)phenylj sulfonyl} (isobutyl)amino]propyl} -3 -methyl-2- { 3 - [(2-methyl- 1,3- thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(5-formyl-2-furyl)sulfonyl](isobutyl)amino]-2- hydroxypropylj -3-methyl-2- {3 -[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({5-[(E)-(hydroxyimino)methyl]-2- firryl}sulfonyl)(isobutyl)aminoJpropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo-l-imidazolidinylJbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({5-[(2)-(hydroxyimino)methyl]-2- furyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo-l-imidazolidinylJbutanamide; (2S)-N-{(lS,2R)-3-[({4- [amino(hydroxyimino)methyl]phenylJ sulfonyl)(isobutyl)aminoj- 1 -benzyl-2-hydroxypropylJ - 3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxoimidazolidin-l-ylJbutanamide; 4-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo- 1 -imidazolidinyl Jbutanoyl)amino]-4- phenylbutylJ(isobutyl)amino]sulfonyl}benzamide; 4- { [[(2R,3S)-2-hydroxy-3 -( {(2S,3S)-3-methyl-2- [2-oxo-3 -(3-pyridinylmethyl)- 1 - imidazolidinyl]pentanoyl}ammo)-4-phenylbutyl](isobutyl)amino]sulfonylJbenzamide; and (2S,3S)-N-{(lS,2R)-l-benzyl-3-[[(4-cyanophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-[2-oxo-3-(3-pyridinyhnethyl)-l-imidazolidinylJpentanamide; or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof. In a fourth embodiment, the present invention provides a compound of formula (IN)
Figure imgf000062_0001
(IN) or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrag, or combination thereof, wherein X is O, S orΝH;
R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl or heteroarylalkyl; wherein each R is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, formyl nitro, hydroxy, alkoxy, -ΝH2, -N(H)alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, haloalkyl, hydroxyalkyl and alkoxyalkyl; Ri is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rla)NRaRb or -OC O)C(H)(Rla)N(H)C(O)ORa; Rla is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each Rιa is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaR , -C(=O)Ra, -NRaR , -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Ra)SO2NRaRb, -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaR , -C(=O)NRaRb and -C(=O)ORa; R2 is H;
R3 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra, -alkylNRaRb, -alkylN(Rb)C(=O)ORa, -alkylN(R )C(=O)Ra, -alkylN(Rb)SO2Ra or -alkylN(Rb)SO2NRaRb; wherein each of the cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the cycloalkenylalkyl, hetrocycle moiety of the heterocyclealkyl, heteroaryl moiety of the heteroarylalkyl, aryl moiety of the arylalkyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), - N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2, -alkylC(=O)alkyl and R3a;
R3a is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, wherein each R a is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH,
-alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2 and
-alkylC(=O)alkyl; i is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl wherein each i is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, alkyl, oxo, alkenyl, alkynyl, nitro, cyano, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, nitroalkyl, -OR4a, -S ia, -SOR4a, -SO^, -NR^I , -OC(-O)R4a, -C(=O)R4a, -C(=O)OR4a, -C(=O)NR4aR4b, -N(R4 )C(=O)R4a, -N(R4b)C O)OR4a, -N(R4b)SO2R4a, -N(R4 )C(=O)NR4aR b, -N(R4b)SO2NR4aR4b, -alkylSRa, -alkylSORa, -alkylSORa, -alkylNR4aR4b,
Figure imgf000063_0001
-alkylN(R4b)C(=O)R4a, -alkylN(R4b)C(=O)OR4a, -alkylN ^SO^a,
-alkylN(R4 )C(=O)NR4aR4b, -al ylN(R4 )SO2NR4aR4 , -N(H)C(=O)alkylN(H)C(=O)
-N(H)C(=O)alkylNR4aR4b, -C(R4 )=NOR4a, -C(NR4aR4b)=NOR4a and
-C(R4b):=NOC(=O)alkylNR4aR4b;
R4a and R b, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl and heteroalkyl; wherein each R a and Rrb, at each occurrence, is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, hydroxy, alkoxy, halo, nitro, cyano, formyl, oxo, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)alkyl, -C(=O)OH, -C(-O)Oalkyl, -C(=O)NH2, -C(=O)N(H)alkyl, -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, cyanoalkyl, nitroalkyl, formylalkyl and alkoxyalkyl; R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; wherein each R7 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, -ORa, -OalkylC(=O)NRaRb, -SRa, -SORa, -SO2Ra, -SO2NRaR , -C(=O)Raj -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Rb)SO2NRaRb, -N(Rb)C(=NH)NRaR , -N(R )C(=O)NRaRb, -C(=O)NRaRb, -C(=O)ORa and R7a; R7a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH,
-C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(-O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyI)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2; Rio is alkyl, alkenyl, alkynyl, -C(=O)NRaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R10 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaR , -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaRb, -N(Rb)SO2NRaRb, -C(=O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaR , -C(alkyl)=NNRaRb, -C(H)(=NORa)NRaRb, -C(alkyl)(=NORa)NRaRb, -alkylN(Rb)NRaRb, -alkylN(R )C(=O)Ra, -alkylN(Rb)C(-O)ORa, -alkylN(Rb)C(=O)NRaRb, -alkylN(Rb)SO2NRaRb, -alkylN(Rb)SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaRb and R10a;
R10a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R10a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyI), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2; Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle; wherein each Ra and Rb, at each occurrence, is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(all yl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH,
-alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and R^ alternatively, Ra and R , together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Re; and
Re is aryl, heteroaryl or heterocycle; wherein each Re is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2,
-N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)2, -alkyl-N(H)C(=O)NH2, -alkyl-N(H)C(=O)N(H)(alkyl), -alkyl-N(H)C(=O)N(alkyl)2, -alkyl-C(=O)OH, -alkyl-C(=O)Oalkyl, -alkyl-C(=O)NH2, -alkyl-C(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2. For example, the present invention provides a compound of formula (IV) wherein Ri is OH and R2 is H. For example, the present invention provides a compound of formula (IV) wherein Ri is OH, R2 is H, X is O and R3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra or -alkylNRaR . For example, the present invention provides a compound of formula (IV) wherein R\ is OH, R2 is H, X is O, R3 is alkyl or cycloalkyl and i is aryl or heteroaryl. For example, the present invention provides a compound of formula (IV) wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkyl and R4 is phenyl. For example, the present invention provides a compound of formula (IV) wherein R\ is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl and t is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OI , -NR4aR and -C(R4b)=NOR a; wherein R4a and R 1, are indepdently selected from the group consisting of hydrogen or alkyl. For example, the present invention provides a compound of formula (IV) wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl, 1^ is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -NRta n, and -C(R b)=NOR a, and R7 is alkyl; wherein ta and R^ are indepdently selected from the group consisting of hydrogen or alkyl. For example, the present invention provides a compound of formula (IV) wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl, R4 is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR , - taRn, and -C(R4 )=NOR4a, R7 is alkyl and R is phenylmethyl; wherein R4a and n, are indepdently selected from the group consisting of hydrogen or alkyl. For example, the present invention provides a compound of formula (IV) wherein Ri is OH, R2 is H, X is O, R3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, R4 is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -O ja, -N ^ ^ and -C(R4b)=NOR4a, R7 is alkyl and R is phenylmethyl; wherein ^ and Rn, are indepdently selected from the group consisting of hydrogen or alkyl. For example, the present invention provides a compound of formula (IV) wherein Ri is OH, R2 is H, X is O, R3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, R is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR^, -NR4aR4b and -C(R4b)=NOR a, R7 is CI alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5 alkyl and R is phenylmethyl; wherein R^ and ft are indepdently selected from the group consisting of hydrogen or alkyl. Exemplary compounds of the present invention of formula (IV) include, but not limited to, the following: (2S)-N- {(1 S,2R)-1 -benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenylJsulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxo-2,3-dihydro-lH-imidazol-l-ylJbutanamide; and (2S,3 S)-N- {(1 S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylJ-2-[3-({2-[N- hydroxy ethanimidoylJpyridin-4-yl J methyl)-2-oxo-2,3 -dihydro- 1 H-imidazol- 1 -yl] -3 - methylpentanamide; or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof. In a fifth embodiment, the present invention provides a compound of formula (V)
Figure imgf000067_0001
or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, wherein X is O, S orNH; Y is O, S or NH;
R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl or heteroarylalkyl; wherein each R is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, formyl, nitro, hydroxy, alkoxy, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, haloalkyl, hydroxyalkyl and alkoxyalkyl; Ri is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rla)NRaRb or -OC(=O)C(H)(Rla)N(H)C(O)ORa; Rla is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each Rla is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaRb, -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Ra)SO2NRaRb, -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaR and -C(=O)ORa; R2 is H;
R3 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra, -alkyINRaRb, -alkylN(Rb)C(=O)ORa, -alkylN(Rb)C(=O)Ra, -alkylN(R )SO2Ra or -alkylN(Rb)S02NRaRb; wherein each of the cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the cycloalkenylalkyl, hetrocycle moiety of the heterocyclealkyl, heteroaryl moiety of the heteroarylalkyl, aryl moiety of the arylalkyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), - N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2,' -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2, -alkylC(=O)alkyl and R3a;
R3a is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, wherein each R3a is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), - -C(O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH,
-alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2 and
-alkylC(=O)alkyl;
Ri is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl wherein each R4 is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, alkyl, oxo, alkenyl, alkynyl, nitro, cyano, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, nitroalkyl, -OR4a, -SR4a, -SO ia, -SO2Rta, -NE J b, -OC(-O)R4a,
Figure imgf000068_0001
-C(=O)OR4a, -C(=O)NR4aR4b, -N(R4b)C(=O)R4a, -N(R4b)C(-O)OR4a, -N(R4b)SO2R4a, -N(R4b)C(=O)NR4aR4b, -N(R4b)SO2NR4aR4b, -alkylSRa, -alkylSORia, -alkylSORa, -alkylNRΛb, -alkylOC(=O)R4a, -alkylC(=O)R4a, -alkylC(=O)OR4a, -alkylC(=O)NR4aR4 , -alkylN(R4 )C(=O)R4a, -alkylN(R4 )C(=O)OR4a, -alkylN(R4b)SO2R4a,
-alkylN(R4 )C(=O)NR4aR4b, -alkylN(R4b)SO2NR4aR4b, -N(H)C(=O)alkylN(H)C(=O)OR4a,
-N(H)C(=O)alkylNR4aR b5 -C(R4 )-NOR4a, -C(NR4aR4b)=NOR4a and
-C(R4b)=NOC(=O)alkylNR4aR4b; ia and R^, at each occurrence, are independently selected from the group consisting of hydrogen, allcyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl and heteroalkyl; wherein each R^ and R b, at each occurrence, is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, hydroxy, alkoxy, halo, nitro, cyano, formyl, oxo, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)alkyl, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)alkyl, -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, cyanoalkyl, nitroalkyl, formylalkyl and alkoxyalkyl; R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; wherein each R7 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, -ORa, -OalkylC(=O)NRaRb, -SRa, -SORa, -SO2Ra, -SO2NRaRb, -C(=O)Ra: -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Rb)SO2NRaRb, -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaRb, -C(=O)ORa and R7a; R7a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH,
-C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2; Rπ is alkyl, alkenyl, alkynyl, -C(=O)NRaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each Rπ is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb, -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaRb, -N(R )SO2NRaRb, -C(=O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(-O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaR , -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaR , -C(alkyl)=NNRaR , -C(H)(=NORa)NRaRb, -C(alkyl)(=NORa)NRaRb, -alkylN(Rb)NRaRb, -alkyIN(Rb)C(=O)Ra, -alkylN(R )C(=O)ORa, -alkylN(Rb)C(=O)NRaRb, -alkylN(Rb)SO2NRaR , -alkylN(Rb)SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaR and Rl la;
Rπa is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each Rl la is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2; Ra and R at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle; wherein each Ra and Rb, at each occurrence, is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(= )N(alkyl)2, -alkylC(=O)OH,
-alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Rcj alternatively, Ra and Rb, together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(-O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(aιkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -aUcylC(-O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Re;
Re is aryl, heteroaryl or heterocycle; wherein each Re is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2,
-N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkyl-N(H)(alkyl), -alkyl-N(allcyl)2, -alkyl-N(H)C(=O)NH2, -alkyl-N(H)C(=O)N(H)(alkyl), -alkyl-N(H)C(=O)N(alkyl)2, -alkyl-C(=O)OH, -alkyl-C(=O)Oalkyl, -alkyl-C(=O)NH2, -alkyl-C(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2; and n is 1 or 2. For example, the present invention provides a compound of formula (V) wherein Ri is OH and R2 is H. For example, the present invention provides a compound of formula (V) wherein Ri is OH, R2 is H, X is O, Y is O and R3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra or -alkylNRaR . For example, the present invention provides a compound of formula (V) wherein R\ is OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkyl and Rt is aryl or heteroaryl. For example, the present invention provides a compound of foπnula (V) wherein Ri is OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkyl and t is phenyl. For example, the present invention provides a compound of formula (V) wherein Ri is
OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkylalkyl and R is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR4a, -NR^Ru, and -C(R4b)=NOR a; wherein ta and u, are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (V) wherein Ri is
OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkylalkyl, i is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR a, -NR^Rn, and -C(R4 )=NOR a, and R7 is alkyl; wherein Ria and tb are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (V) wherein Ri is
OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkylalkyl, i is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -NR^RH, and -C(R4b)=NOR a, R is alkyl and R is phenylmethyl; wherein ta and Rib are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (V) wherein Ri is
OH, R2 is H, X is O, Y is O, R3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, Rt is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -N taRu, and -C(Rtb)=NOR4a, R7 is alkyl and R is phenylmethyl; wherein R4a and tb are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (V) wherein Ri is OH, R2 is H, X is O, Y is O, R3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, Rt is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, - Rtal tt, and -C(R4b)=NOR4a, R7 is CI alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5 alkyl and R is phenylmethyl; wherein ta and u, are independently selected from the group consisting of hydrogen and alkyl. Exemplary compounds of the present invention of formula (V) include, but not limited to, the following: (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyljphenylj sulfonyl)(isobutyl)amino]propyl} -2-(3 - { [2-(methoxymethyl)- l,3-thiazol-4-yl]methyl}-2,4-dioxo-l-imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]ρhenyl}sulfonyl)(isobutyl)amino]propylJ-3-methyl-2-[3-(3- nitrobenzyl)-2,4-dioxo- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylJ-3-methyl-2-{3-[(l-methyl- lH-benzimidazol-2-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (lιydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylJ-2-[2,4-dioxo-3-(2- quinolinylmethyl)- 1 -imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylJ-3-methyl-2-{3-[(3-methyl- 3H-imidazo[4,5-b]pyridin-2-yl)methyl]-2,4-dioxo-l-iιnidazolidinyl}butanamide; (2S)-2-[3-(l,3-benzodioxol-5-ylmethyl)-2,4-dioxo-l-imidazolidinyl]-N-{(lS,2R)-l- benzyl-2-hydroxy-3-[( {4-[(E)~ (hydroxyimino)methyl]phenylJ sulfonyl)(isobutyl)amino]propyl} -3-methylbutanamide; 2-(3-benzyl-2,4-dioxo-l-imidazolidinyl)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyljphenylj sulfonyl)(isobutyl)amino]propyl} acetamide; , (2S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[2,4-dioxo-3-(4- pyridinylmethyl)-l-imidazolidinylj-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyljphenylJsulfonyl)(isobutyl)amino]propyl}-2-[3-({2- [(dimethylamino)methylj - 1 ,3 -thiazol-4-yl J methyl)-2,4-dioxo- 1 -imidazolidinyl] -3 - methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylJ-3-methyl-2-{3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenylJ sulfonyl)amino]-2 -hydroxypropyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[2,4-dioxo-3-(2- pyridinylmethyl)- 1 -imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl}-3-methyl-2- {3-[(6-methyl- 2-pyridinyl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2 )-2-(3-benzyl-2,4-dioxo-l-imidazolidinyl)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylbutanamide; (2S)-2-[3-(3-acetylbenzyl)-2,4-dioxo-l-imidazolidinyl]-N-{(lS,2R)-l-benzyl-2- hydroxy-3-[({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-(3-{[2- (methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} -2,4-dioxo- 1 -imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (26)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hyαLxOxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-(3-{[2- (methoxymethyl)-l ,3-thiazol-4-yl]methyl} -2,4-dioxo- 1 -imidazolidinyl)-3-methylbutanamide; (2S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2- {3-[(2-cyano-4- pyridinyl)methyl]-2,4-dioxo-l-imidazolidinyl}-3-methylbutanamide; (2S)-2-{3-[(2-acetyl-4-pyridinyl)methyl]-2,4-dioxo-l-imidazolidinyl}-N-{(lS,2R)-l- benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3 -methylbutanamide; (2S)-2- {3 -[3-(azidomethyl)benzyl]-2,4-dioxo- 1 -imidazolidinyl} -N- {( 1S,2R 1 -benzyl- 2-hydroxy-3-[({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)ammo]propyl}-3- methylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-[2,4-dioxo-3-(4- pyridinylmethyl)-l-imidazolidinyl]-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[2,4-dioxo-3-(3- pyridinylmethyl)-l-imidazolidinyl]-3-methylpentanamide; (2S,3S)-2-(3- { [2-(acetylamino)- 1 ,3-thiazol-4-yl]methyl} -2,4-dioxo- 1 -imidazolidinyl)-
N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methylpentanamide; (2S,3S)-2-(3-{[2-(acetylamino)-l,3-thiazol-4-yl]methyl}-2,4-dioxo-l-imidazolidinyl)- N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]ρhenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[2,4-dioxo-3-(2- pyrazinylmethyl)- 1 -imidazolidinyl]-3-methylbutanamide; (2S)-2-(3- { [2-(acetylamino)- 1 ,3-thiazol-4-yl]methyl} -2,4-dioxo- 1 -imidazolidinyl)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2-(3- {3- [(methylamino)methyl]benzyl} -2,4-dioxo- 1 -imidazolidinyl)butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[3-(3- nitrobenzyl)-2,4-dioxo- 1 -imidazolidinyl]pentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[2,4-dioxo-3-(4- quinolinylmethyl)-l-imidazolidinyl]-3-methylbutanamide; (2S,3S)-2-{3-[(6-amino-2-quinolinyl)methyl]-2,4-dioxo-l-imidazolidinyl}-N- {(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S,3S)-2-{3-[(2-acetyl-4-pyridinyl)methyl]-2,4-dioxo-l-imidazolidinyl}-N-{(lS,2R)- l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S,3S)-2-(3-{[2-(acetylamino)-l,3-thiazol-4-yl]methyl}-2,4-dioxo-l-imidazolidinyl)- N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methylpentanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(3- methyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -3-methyl-2- {3-[(3- methyl-3Hr-imidazo[4,5-b]pyridin-2-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-[2,4-dioxo-3 -(2- pyridinylmethyl)-l-imidazolidinyl]-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[2,4-dioxo-3-(4- quinolinylmethyl)- 1 -imidazolidinyl] -3 -methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutyhnethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-[2,4-dioxo-3-(4- quinolinylmethyl)-l-imidazolidinyl]-3-methylpentanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-3-[(cyclopentylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-[2,4-dioxo-3-(4- quinolinylmethyl)-l-imidazolidinyl]-3-methylpentanamide; (2S)-2-[3-(3-aminobenzyl)-2,4-dioxo-l-imidazolidinyl]-Ν-{(lS,2R)-l-benzyl-2- hydroxy-3-[( {4-[(Ε)-(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3- methylbutanamide; (2S)-N-{(1 S,2R)-1 -benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3- {3-[N- hydroxyethanimidoyl]benzyl} -2,4-dioxo- 1 -imidazolidinyf)-3 -methylbutanamide; (2S)-2-{3-[3-(aminomethyl)benzyl]-2,4-dioxo-l-imidazolidinyl}-N-{(lS,2R)-l- benzyl-2-hydroxy-3-[( {4-[(E (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methylbutanamide; (2S,3S)-2-[3-(3-aminobenzyl)-2,4-dioxo-l-imidazolidinyl]-N-{(lS,2R)-l-benzyl-2- hydroxy-3-[( {4-[(E)-(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3- methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({2-[N- hydroxyethanimidoyl]-4-pyridinyl}methyl)-2,4-dioxo-l-imidazolidinyl]-3- methylpentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2,4-dioxo- 1 -imidazolidinyl} butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino }propyl)-2-(3- { [2-(methoxymethyl)- 1 ,3 -thiazol-4-yl]methyl} - 2,4-dioxo- 1 -imidazolidinyl)-3 -methylbutanamide; (2S)-2-(3-benzyl-2,4-dioxo-l-imidazolidinyl)-N-((lS,2R)-l-benzyl-2-hydroxy-3- {isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-[2,4-dioxo-3-(2-quinolinylmethyl)-l- imidazolidinyl] -3 -methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(l-methyl-lH-benzimidazol-2- yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; ethyl [3-((lS)-l-{[((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)amino]carbonyl}-2-methylpropyl)-2,5-dioxo-l- imidazolidinyl]acetate; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(3-methyl-3H-imidazo[4,5- b]pyridin-2-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isoburyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(6-methoxy-2-quinolinyl)methyl]-2,4-dioxo- 1 -imidazolidinyl} -3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-[2,4-dioxo-3-(4-quinolinylmethyl)-l- imidazolidinyl] -3 -methylbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(6-nitro-2-quinolinyl)methyl]-2,4- dioxo- 1 -imidazolidinyl}butanamide; (2S)-2-{3-[(6-amino-2-quinolinyl)methyl]-2,4-dioxo-l-imidazolidinyl}-N-((lS,2R)-l- benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylbutanamide; (2S)-2-(3- { [2-(acetylamino)- 1 ,3 -thiazol-4-yl]methyl} -2,4-dioxo- 1 -imidazolidinyl)-N- ((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylbutanamide; (2S,3S)-2-(3-{[2-(acetylamino)-l,3-thiazol-4-yl]methyl}-2,4-dioxo-l-imidazolidinyl)- N-(( 1 S,2R)- 1 -benzyl-2-hydroxy-3 - {isobutyl[(4-methoxyphenyl)sulfonyl] amino } propy l)-3 - methylpentanamide; (2S,3S)-2-{3-[(6-amino-2-quinolinyl)methyl]-2,4-dioxo-l-imidazolidinyl}-N-
(( 1 S,2R)- 1 -benzyl-2-hydroxy-3 - {isobutyl[(4-methoxyphenyl)sulfonyl] amino } propy l)-3 - methylpentanamide; (2S 3S)-N-((1S,2R)- 1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-[2,4-dioxo-3-(4-quinolinylmethyl)-l- , imidazolidinyl]-3-methylpentanamide; (25, 3S)-N-((1S,2R)- 1 -benzyl-3- {(cyclopentylmethyl)[(4- methoxyphenyl)sulfonyl] amino} -2-hydroxypropyl)-2-(3 - { [2-(methoxymethyl)- 1 ,3 -thiazol-4- yl]methyl}-2,4-dioxo-l-imidazolidinyl)-3-methylpentanamide; (2S 3S)-N-((1S,2R)- 1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4-yl]methyl}- 2,4-dioxo-l-imidazolidinyl)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- methoxyphenyl)sulfonyl] (neopentyl)amino]propyl} -2-(3 - { [2-(methoxymethyl)- 1 ,3-thiazol-4- yl]methyl}-2,4-dioxo-l-imidazolidinyl)-3-methylpentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}proρyl)-2-{3-[2-(isopropylamino)-2-oxoethyl]-2,4-dioxo-l- imidazolidinyl}-3-methylbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[2-(isobutylamino)-2-oxoethyl]-2,4-dioxo-l- imidazolidinyl}-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[2-(4-morpholinyl)-2-oxoethyl]-2,4- dioxo-l-imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[2-(dimethylamino)-2-oxoethyl]-2,4-dioxo-l- imidazolidinyl} -3 -methylbutanamide; (2S)-2-[3-(2-anilino-2-oxoethyl)-2,4-dioxo-l-imidazolidinyl]-N-((lS,2R)-l-benzyl-2- hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-2-{3-[(2-ethyl-l,3-thiazol-4-yl)methyl]- 2,4-dioxo- 1 -imidazolidinyl} -3 -methylbutanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2- {3-[(2-ethyl- 1 ,3-thiazol-4-yl)methyl]-2,4-dioxo- 1 -imidazolidinyl} -3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2- {3-[(2-ethyl-l ,3-thiazol-4-yl)methyl]-2,4-dioxo- 1 -imidazolidinyl} -3- methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N- {(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l -benzyl-2- hydroxypropyl} -3-methyl-2- {3-[(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2,4-dioxo- 1 - imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-hydroxyphenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl} -3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2,4-dioxo-l - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropylj -2-(3 - { [2-(methoxymethyl)- 1 ,3-thiazol-4-yl]methylJ -2,4-dioxo- 1 - imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4- yl]methylj -2,4-dioxo- 1 -imidazolidinyl)-3-methylbutanamide; (2 )-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl] (isobutyl)amino]propylJ -2-(3- { [2-(methoxymethyl)- 1 ,3 -thiazol-4- yl]methyl}-2,4-dioxo-l-imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4-yl]methyl}-2,4-dioxo-l- imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2-(3 -benzyl-2,4-dioxo- 1 -imidazoiidinyl)-3 -methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-[3-(3-methylbenzyl)-2,4-dioxo-l-imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[3-(2-cyanobenzyl)-2,4-dioxo-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-[3-(3-nitrobenzyl)-2,4-dioxo-l-imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2- {2,4-dioxo-3-[3-(trifluoromethoxy)benzyl]-l -imidazolidinyl} -3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{2,4-dioxo-3-[4-(trifluoromethoxy)benzyl]-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-[3-(4-methylbenzyl)-2,4-dioxo-l-imidazolidinyl]butanamide; (2S)-N- {(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]- 1 -benzyl-2- hydroxypropyl}-3-methyl-2-[3-(4-nitrobenzyl)-2,4-dioxo-l-imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[2,4-dioxo-3-(2-quinolinylmethyl)-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(l-methyl-lH-benzimidazol-2-yl)methyl]-2,4-dioxo-l- imidazolidinyljbutanamide; (2S)rN-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropylj -2-[3 -([1,1 '-biphenyl]-4-ylmethyl)-2,4-dioxo- 1 -imidazolidinyl]-3 - methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[3-(4-benzoylbenzyl)-2,4-dioxo-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-[3-(l-naphthylmethyl)-2,4-dioxo-l-imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-[3-(2-naphthylmethyl)-2,4-dioxo-l-imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[2,4-dioxo-3-(4-vinylbenzyl)-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-[3-(4-methyl-3-nitrobenzyl)-2,4-dioxo-l- imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropylJ-3-methyl-2-[3-(2-nitrobenzyl)-2,4-dioxo-l-imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropylJ-3-methyl-2-[3-(2-methyl-3-nitrobenzyl)-2,4-dioxo-l- imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropylJ-2-{2,4-dioxo-3-[4-(l,2,3-thiadiazol-4-yl)benzyl]-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropylj -2- [2,4-dioxo-3 -(3 -pyridinylmethyl)- 1 -imidazolidinyl] -3 -methylbutanamide; (2S)-N- {(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l -benzyl-2- hydroxypropyl}-2-[2,4-dioxo-3-(2-pyridinylmethyl)-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[2,4-dioxo-3-(4-pyridinylmethyl)-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropylJ-2-[3-(2-methoxy-5-nitrobenzyl)-2,4-dioxo-l-imidazolidinyl]-3- methylbutanamide; (25)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[3-(2-fluoro-6-nitrobenzyl)-2,4-dioxo-l-imidazolidinyl]-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropylJ-3-methyl-2-[3-(3-methyl-4-nitrobenzyl)-2,4-dioxo-l- imidazolidinyl]butanamide; (2S)-N- {(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]- 1 -benzyl-2- hydroxypropyl J -2- {3-[3-(methoxymethyl)benzyl]-2,4-dioxo- 1 -imidazolidinyl} -3- methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(l-methyl-lH-benzimidazol- 2-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[3-(3-bromobenzyl)-2,4-dioxo-l-imidazolidinyl]-3-methylbutanamide; (2S)-2-[3-(3-acetylbenzyl)-2,4-dioxo-l-imidazolidinyl]-N-{(lS,2R)-3-[[(3-amino-4- chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-hydroxypropyl}-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{2,4-dioxo-3-[3-(2-pyrazinyl)benzyl]-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{2,4-dioxo-3-[3-(2-thienyl)benzyl]-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -3 -methyl-2- {3 - [(5 -nitro-3 -thienyl)methyl] -2,4-dioxo- 1 - imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-2-{3-[(6-chloro-l,3-benzodioxol-5- yl)methyl] -2,4-dioxo- 1 -imidazolidinyl} -3 -methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[3-(l,3-benzothiazol-2-ylmethyl)-2,4-dioxo-l-imidazolidinyl]-3- methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl} -3-methyl-2- {3-[(6-nitro-l ,3-benzodioxol-5- yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2»S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxyρroρyl}-3-methyl-2-{3-[(3-methyl-3H-imidazo[4,5-b]ρyridin-2-yl)methyl]-2,4- dioxo-l-imidazolidinyl}butanamide; (2S)-2-[3-(l ,3-benzodioxol-5-ylmethyl)-2,4-dioxo- 1 -imidazolidinyl] -N- {(1 S,2R)- 1 - benzyl-2-hydroxy-3-[[(4-hydroxy-3-methylphenyl)sulfonyl](isobutyl)amino]propyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobuxyl)amino]propyl}-3-methyl-2-{3-[(l-methyl-lH- benzimidazol-2-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]ρropyl}-2-[2,4-dioxo-3-(2-pyridinylmethyl)-l- imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]proρyl} -3-methyl-2- {3-[(6-methyl-2- pyridinyl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(4-methyl-3- p)τidinyl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-2-(3- { [2-(acetylamino)- 1 ,3-thiazol-4-yl]methyl} -2,4-dioxo- 1 -imidazolidinyl)-N-
{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-2-{3-[(2-cyano-4-pyridinyl)methyl]-2,4- dioxo- 1 -imidazolidinyl} -3-methylbutanamide; (2S)-2-{3-[(2-acetyl-4-pyridinyl)methyl]-2,4-dioxo-l-imidazolidinyl}-N-{(lS,2R)-l- benzyl-2-hydroxy-3-[[(4-hydroxy-3-methylphenyl)sulfonyl](isobutyl)amino]propyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{3-[3-(hydroxymethyl)benzyl]-2,4-dioxo-l-imidazolidinyl}-3- methylbutanamide; (2S5S)-2-(3-{[2-(acetylamino)-l,3-thiazol-4-yl]methyl}-2,4-dioxo-l-imidazolidinyl)- N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-
2-hydroxypropyl}-2-{3-[(6-amino-2-quinolinyl)methyl]-2,4-dioxo-l-imidazolidinyl}-3- methylpentanamide; (2S5S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl}-2-[2,4-dioxo-3-(4-quinolinylmethyl)-l-imidazolidinyl]-3- methylpentanamide; and (2S)-N-{(lS,2R)-3-[{[4-((E)-{[(3- aminopropanoyl)oxy]imino}methyl)phenyl]sulfonyl}(cyclopentylmethyl)amino]-l-benzyl-2- hydroxypropyl} -3-methyl-2- {3-[(2 -methyl- 1 ,3 -thiazol-4-yl)methyl] -2,4-dioxo- 1 - imidazolidinyl} butanamide; or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof. In a sixth embodiment the present invention provides a compound of formula (NI)
Figure imgf000082_0001
(NI) or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrag, or combination thereof, wherein X is O, S or ΝH;
R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl or heteroarylalkyl; wherein each R is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, formyl, nitro, hydroxy, alkoxy, -ΝH2, -N(H)alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, haloalkyl, hydroxyalkyl and alkoxyalkyl; Ri is H and R2 is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rιa)NRaRb or -OC(=O)C(H)(Ria)N(H)C(O)ORa; or
Ri is ORa, -OSO2Ra, -OSOsRa, -OPO3Ra, -OC(=O)C(H)(Rιa)NRaRb or -OC(=O)C(H)(Rla)N(H)C(O)ORa; Rla is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each Rιa is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaRb, -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Ra)SO2NRaRb, -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaRb and -C(=O)ORa; R2 is H;
R3 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra, -alkylNRaRb, -alkylN(Rb)C(=O)ORa, -alkylN(Rb)C(=O)Ra, -alkylN(Rb)SO2Ra or -alkylN(R )SO2NRaRb; wherein each of the cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the cycloalkenylalkyl, hetrocycle moiety of the heterocyclealkyl, heteroaryl moiety of the heteroarylalkyl, aryl moiety of the arylalkyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), - N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS (allcyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(allcyl)C(=O)allcyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl),
Figure imgf000083_0001
-alkylC(=O)alkyl and R3a;
R3a is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, wherein each R3a is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O) H2, -C(=O)N(H)(alkyl), -C(O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alky]N(alkyl)C(=O)alkyl, -alkylC(=O)OH,
-alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2 and
-alkylC(=O)alkyl;
R4 is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl wherein each R4 is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, alkyl, oxo, alkenyl, alkynyl, nitro, cyano, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, nitroalkyl, -OR4a, -SRta, -SOI , -SO2Rta, -N 4a 4b, -OC(=O)R4a, -C(=O)R4a, -C(=O)OR4a, -C(=O)NR4aR4b, -N(R4b)C(=O)R4a, -N(R4b)C(=O)OR4a, -N(R4b)SO2R4a, -N(R4 )C(=O)NR4aR4 , -N(R4 )Sθ2N 4a 4b, -alkylSRta, -alkylSORta, -alkylSO2Rta, -alkylNR4aR4b, -alkylOC(=O)R4a, -alkylC(=O)R4a, -alkylC(=O)ORta, -alkylC(=O)NR aR4b,
Figure imgf000083_0002
-alkylN(R4b)SO2Rta,
-alkylN(R4b)C(=O)NR4aR b, -alkylN(R4b)SO2NR4aR4b, -N(Η)C(=O)alkylN(H)C(=O)OR^
-N(H)C(=O)alkylNRtaRt , -C(R4 )=NOR4a, -C(NR4aR4b)=NOR4a and
-C(R4 )=NOC(=O)alkylNR4aR4 ;
R4a and I tb, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl and heteroalkyl; wherein each ta and tb, at each occurrence, is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, hydroxy, alkoxy, halo, nitro, cyano, formyl, oxo, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)alkyl, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)alkyl, -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, cyanoalkyl, nitroalkyl, formylalkyl and alkoxyalkyl;
R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; wherein each R7 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, -ORa, -OalkylC(=O)NRaRb, -SRa, -SORa, -SO2Ra, -SO2NRaR , -C(=O)Ra, -NRaRh, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Rb)SO2NRaRb, -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaRb, -C(=O)ORa and R7a; R7a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH,
-C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2; R12 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or cycloalkenylalkyl; wherein each R12 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, alkoxy cyano, nitro and halo;
R13 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherem each R13 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb, -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(R )C(=O)ORa, -N(Rb)C(=O)NRaR , -N(Rb)SO2NRaRb, -C(=O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaR , -C(alkyl)=NNRaRb,
-C(H)(=NORa)NRaRb, -C(alkyl)(=NORa)NRaRb, -alkylN(Rb)NRaRb, -alkylN(Rb)C(=O)Ra, -alkylN(Rb)C(=O)ORa, -alkylN(Rb)C(=O)NRaRb, -alkylN(Rb)SO2NRaR , -alkylN(Rb)SO2Ra, -alkylC(=O)Ra, -alkylC(-O)ORa, -alkylC(=O)NRaR and R13a; Ri3a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R13a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2; Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle; wherein each Ra and Rb, at each occurrence, is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2,
-alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Re; alternatively, Ra and Rb, together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl),
-alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Re; and
Re is aryl, heteroaryl or heterocycle; wherein each Re is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C=O)Oalkyl, -C(=O)NH2, -C(-O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)2, -alkyl-N(H)C(=O)NH2, -alkyl-N(H)C(=O)N(H)(alkyl), -alkyl-N(H)C(=O)N(alkyl)2, -alkyl-C(=O)OH, -alkyl-C(=O)Oalkyl, -alkyl-C(=O)NH2, -alkyl-C(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2. For example, the present invention provides a compound of formula (VI) wherein R\ is OH and R2 is H. For example, the present invention provides a compound of formula (VI) wherein \ is OH, R2 is H, X is O and R3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra or -alkylNRaR . For example, the present invention provides a compound of formula (VI) wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkyl and Rt is aryl or heteroaryl. For example, the present invention provides a compound of formula (VI) wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl and R4 is phenyl. For example, the present invention provides a compound of formula (VI) wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl, t is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -NR aR4b and -C(Rt )=NOR a, and R is alkyl; wherein Rta and tb are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (VI) wherein R\ is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl, R is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR^, -N ta tb and -C(R )=NOR4a, R7 is alkyl and R12 is alkyl; wherein ta and Rtb are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (VI) wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl, Rt is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -NR^R^ and -C(R4b)=NOR a, R7 is alkyl, R12 is alkyl and R is phenylmethyl; wherein ta and Rtb are independently selected from the group consisting of hydrogen and alkyl. ' For example, the present invention provides a compound of formula (VI) wherein Ri is OH, R2 is H, X is O, R3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, t is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR^, - E ta u, and -C(R b)=:NOR4a, R7 is alkyl, R12 is methyl or ethyl, and R is phenylmethyl; wherein R a and R^ are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (VI) wherein Ri is OH, R2 is H, X is O, R3 is C3 alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, t is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, - aRtb and -C(R4 )=NOR4a, R7 is CI allcyl, C2 alkyl, C3 alkyl, C4 alkyl or C5 alkyl, R12 is methyl or ethyl, and R is phenylmethyl; wherein R4a and R b are independently selected from the group consisting of hydrogen and alkyl. Exemplary compounds of the present invention of fonnula (VI) include, but not limited to, the following: (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-({[methyl(2- pyridinylmethyl)amino]carbonyl}amino)pentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-( { [[(2-isopropyl- 1,3- thiazol-4-yl)methyl](methyl)amino]carbonyl}amino)-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2-( {[methyl(2- pyridinylmethyl)amino]carbonyl}amino)butanamide; (2S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3 -methyl-2- [( {methyl[(2- methyl-l,3-thiazol-4-yl)methyl]amino}carbonyl)amino]butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-( { [ { [2-(methoxymethyl)- l,3-thiazol-4-yl]methyl}(methyl)amino]carbonyl}amino)-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-[( {ethyl[(2-isopropyl-l ,3- thiazol-4-yl)methyl]amino}carbonyl)amino]propanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -2-( { [ [(2-isopropyl- 1,3- thiazol-4-yl)methyl](methyl)amino]carbonyl} amino)-3-methylbutanamide; (2S)-N- {(1S,2R)- 1 -benzyl-3-[(cyclobutylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-({[[(2-isopropyl-l,3- thiazol-4-yl)methyl](methyl)amino]carbonyl}amino)-3-methylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -3 -methyl-2-( { [methyl(2- p3^ridinylmethyl)amino]carbonyl}amino)pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-({[methyl(2- p3αidinylmethyl)amino]carbonyl}amino)pentanamide; (2S,3R)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-tert-butoxy-2-({[{[2- (methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} (methyl)amino]carbonyl} amino)butanamide; (2S,3R)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-tert-butoxy-2-({[{[2- (methoxymethyl)- 1 ,3 -thiazol-4-yl]methyl} (methyl)amino]carbonyl} amino)butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -2-( { [ { [2- (methoxymethyl)-l,3-thiazol-4-yl]methyl}(methyl)amino]carbonyl}amino)-3- methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -2-( { [ { [2- (methoxymethyl)-l,3-thiazol-4-yl]methyl}(methyl)amino]carbonyl}amino)-3- methylpentanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -3-methyl-2-[( {methyl[(2- methyl-l,3-thiazol-4-yl)methyl]amino}carbonyl)amino]butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3 -methyl-2- [( {methyl[(2- methyl- 1 ,3 -thiazol-4-yl)methyl] amino } carbonyl)amino]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2 -hydroxypropyl} -3-methyl-2-[({methyl[(2- methyl-l,3-thiazol-4-yl)methyl]amino}carbonyl)amino]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-tert-butoxy-2- [({methyl[(2-methyl-l,3-tliiazol-4-yl)methyl]amino}carbonyl)amino]butanamide; (2S,3»S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-tert-butoxy-2- [({methyl[(2-methyl-l,3-thiazol-4-yl)methyl]amino}'carbonyl)amino]butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]ρhenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-({[methyl(3- nitrobenzyl)amino]carbonyl} amino)pentanamide; methyl 4-{(5S,8S,9R)-8-benzyl-9-hydroxy-l l-({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)-2, 13-dimethyl-5-[(lS)- 1 -methylpropyl]-3,6-dioxo- 2,4,7, 11 -tetraazatetradec- 1 -yl} - 1 ,3-thiazol-2-ylcarbamate; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutyhnethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -2-( { [ { [2- (methoxymethyl)-l,3-thiazol-4-yl]methyl}(methyl)amino]carbonyl}amino)-3- methylbutanamide; (2S,3S)-2-({[{[2-(acetylamino)-l,3-thiazol-4- yl]methyl}(methyl)amino]carbonyl}amino)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4- [(E)-(hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -3- methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-({[methyl(3- pyridinylmethyl)amino]carbonyl}amino)pentanamide; (2S,3S)-N- {(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -3-methyl-2-( {[methyl(4- pyridinylmethyl)amino]carbonyl}amino)pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenylJ sulfonyl)(isobutyl)amino]propyl J -2-( { [ { [2-(methoxymethyl)- 1 ,3-thiazol-4-yl]methylJ (methyl)amino]carbonyl J amino)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-({[{[6- (methoxymethyl)-2-pyridinyl]methyl}(methyl)amino]carbonylJamino)-3- methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylJ-2-({[[(2-isopropyl-l,3- thiazol-4-yl)methyl](methyl)amino] carbonyl J amino)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-({[[(2-isopropyl-l,3- thiazol-4-yl)methyl](methyl)amino]carbonyl}amino)-3-methylpentanamide; (2S,3S)-2-({[({6-[(Z)-amino(hydroxyimino)methyl]-2- pyridinyl}methyl)(methyl)amino]carbonyl}amino)-N-{(lS,2R)-l-benzyl-3-
[(cyclopentylmethyl)({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2- hydroxypropyl J -3-methylpentanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentyhnethyl)({4-[(E)- (hydroxyimino)methyl]phenylJsulfonyl)amino]-2-hydroxypropyl}-2-({[{[6- (methoxymethyl)-2-pyridinyl]methylJ (methyl)amino]carbonylJ amino)-3,3- dimethylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenylJ sulfonyl)amino]-2 -hydroxypropyl} -2-( { [ { [6-(tert- butoxymethyl)-2-pyridinyl]methyl}(methyl)amino]carbonyl}amino)-3,3- dimethylbutanamide; (2S,3R)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -3-hydroxy-2-( { [ {[2- (methoxymethyl)-l,3-thiazol-4-yl]methyl}(methyl)amino]carbonyl}amino)butanamide; (2S,3R)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -3 -hydroxy-2-( { [ { [2- (methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} (methyl)amino]carbonyl} amino)butanamide; (2S,3S)-2-({[(3-aminobenzyl)(methyl)amino]carbonyl}amino)-N-{(lS,2R)-l-benzyl- 2-hydroxy-3 - [( {4-[(E)-(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3 - methylpentanamide; (2S,3R)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-hydroxy-2-[({methyl[(2- methyl-l,3-thiazol-4-yl)methyl]amino}carbonyl)amino]butanamide; (2S,3R)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropylJ-3-hydroxy-2- [({methyl[(2-methyl-l,3-thiazol-4-yl)methyl]aminoJcarbonyl)amino]butanamide; (2S,3S)-2-({[{[2-(aminomethyl)-l,3-thiazol-4- yl]methylj (methyl)amino]carbonylJ amino)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylJ-3-methylpentanamide; (2S,3S)-2-({[{[2-(aminomethyl)-l,3-thiazol-4- yl]methyl J (methyl)amino]carbonylJ amino)-N- {(1 S,2R)- 1 -benzyl-3 - [(cyclobutylmethyl)( {4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropylJ-3- methylpentanamide; (2S,3S)-2-({[{[2-(aminomethyl)-l,3-thiazol-4- yl]methyl}(methyl)amino]carbonylJamino)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropylJ-3- methylpentanamide; (2S,3S)-2-({[({2-[(lS)-l-aminoethyl]-l,3-thiazol-4- yl}methyl)(methyl)amino]carbonylJamino)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-
[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3- methylpentanamide; (2S,3S)-2-({[({2-[(lR)-l-aminoethyl]-l,3-thiazol-4- ylJmethyl)(methyl)amino]carbonyl}amino)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3- methylpentanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-3-[(cyclopentylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenylJsulfonyl)amino]-2-hydroxypropylJ-2-({[({6-[N- hydroxyethanimidoyl]72-pyridinyl}methyl)(methyl)amino]carbonyl}amino)-3- methylpentanamide; and (2S,3S)-2-( {[( {2-[(lS}- 1 -(acetylamino)ethyl]-l ,3-thiazol-4- yl}methyl)(methyl)amino]carbonylJ amino)-N- {(1S,2R)- 1 -benzyl-3-[(cyclopentylmethyl)( {4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropylJ-3- methylpentanamide; or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof. In a seventh embodiment, the present invention provides a compound of formula
Figure imgf000090_0001
(NH) or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, wherein:
A is R5C(O , R6SO2-,
Figure imgf000091_0001
X is O, S or ΝH; Y is O, S or ΝH; ,
R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl or heteroarylalkyl; wherein each R is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, formyl, nitro, hydroxy, alkoxy, -ΝH , -N(H)alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, haloalkyl, hydroxyalkyl and alkoxyalkyl; Ri is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rla)NRaR or -OC(=O)C(H)(Rla)N(H)C(O)ORa;
Rla is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each Rla is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -ORa, -SRa, -SORa,
-SO2Ra, -SO2NRaRb, -C(=O)Ra, -NRaR , -N(Rb)C O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Ra)SO2NRaRb, -N(Rb)C(-NH)NRaRb, -N(Rb)C(=O)NRaR , -C(=O)NRaRb and -C(=O)ORa; R2 is H; R3 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra, -alkylNRaR , -alkylN(Rb)C(=O)ORa, -alkylN(R )C(=O)Ra, -alkylN(R )SO2Ra or -alkylN(Rb)SO2NRaRb; wherein each of the cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the cycloalkenylalkyl, hetrocycle moiety of the heterocyclealkyl, heteroaryl moiety of the heteroarylalkyl, aryl moiety of the arylalkyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), - N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyI), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(-O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2, -alkylC(-O)alkyl and R3a; R3a is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, wherein each R3a is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O) alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2 and -alkylC(=O)alkyl; R4 is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl wherein each t is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, alkyl, oxo, alkenyl, alkynyl, nitro, cyano, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, nitroalkyl, -ORta, -SRta, -SORta, -SO2Rta, -N ^ Λ, -OC(=O)R4a, -C(=O)R4a, -C(=O)ORta,
Figure imgf000092_0001
-N(R4 )C(=O)NR4aR4b, -N(R4b)SO2NR aR b, -alkylSRta, -alkylSOR4a, -alkylSO2Rta, -alkylNI taRti,, -alkylOC^O)!^, -alkylC(=O)Rta, -alkylC(=O)OR4a, -alkylC(=O)NR4aR4b,
Figure imgf000092_0002
-alkylN(Rtb)SO2Rta, -alkylN(R4b)C(-O)NR4aR4b, -alkylN(R4 )SO2NR4aR4b, -N(H)C(=O)alkylN(H)C(=O)OR4a, -N(H)C(=O)alkylNR4aR4 , -C(R4 )=NOR4a, -C(NR4aR4b)=NOR4a and -C(R4 )=NOC(=O)alkylNR4aR4b; R4a and Rtb, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl and heteroalkyl; wherein each Rta and tb, at each occurrence, is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, hydroxy, alkoxy, halo, nitro, cyano, formyl, oxo, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)allcyl, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2,
-C(=O)N(H)allcyl, -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, cyanoalkyl, nitroalkyl, formylalkyl and alkoxyalkyl; Rs is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -OalkylSO2alkyl, -O-heterocycle, -alkyl-O-aryl or -O-alkyl-heteroaryl; wherein the heterocycle, aryl or heteroaryl moiety of -O-heterocycle, -alkyl-O-aryl and -O-alkyl-heteroaryl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(-O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(==O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
R6 is aryl or heteroaryl; wherein each R6 is substituted with 0 or 1 substituent selected from the group consisting of-C(H)=NOH, -C(alkyl)=NOH, -C(H)=NO(alkyl), -C(alkyl)=NO(alkyl), -C(H)=NO(arylalkyl) and -C(alkyl)=NO(arylalkyl);
R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; wherein each R7 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, -ORa, -OalkylC(=O)NRaR , -SRa, -SORa, -SO2R3, -SO2NRaRb, -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Rb)SO2NRaRb, -N(R )C(=NH)NRaRb, -N(R )C(=O)NRaR , -C(=O)NRaRb, -C(=O)ORa and R7a; R7a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R7a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH,
-C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(==O)N(H)(alkyl) and -alkyl-C(-O)N(alkyl)2; R8 is -C(=O)OR8a or -C(=O)alkylNR8aR8 ,
R8a and R8b are, at each occurrence, independently selected from the group consisting of allcyl, arylalkyl and heteroarylalkyl; wherein each R8a and R8b is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of alkyl, nitro, hydroxy, alkoxy, amino, formyl, halo, haloalkyl, hydroxyalkyl, alkoxyalky aminoalkyl and formylalkyl;
R9 is alkyl, alkenyl, alkynyl, -C(=O)NRaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R9 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SOR,, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb, -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(R )C(=O)NRaR , -N(R )SO2NRaRb, -C(=O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(alkyl)=NNRaR , -C(H)(=NORa)NRaR , -C(alkyl)(=NORa)NRaR , -alkylN(Rb)NRaR , -alkylN(Rb)C(=O)Ra, -alkylN(Rb)C(=O)ORa, -alkylN(Rb)C(=O)NRaRb, -alkylN(Rb)SO2NRaRb, -alkylN(R )SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaRb and R9a;
R9a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH,
-C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(-O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
Rio is alkyl, alkenyl, alkynyl, -C(=O)NRaR , -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R10 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb, -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaRb,
-N(R )SO2NRaRb, -C(=O)Ra, -C(=O)NRaR , -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -allcylSO2ORa, -alkylNRaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(alkyl)=NNRaR , -C(H)(=NORa)NRaRb, -C(alkyl)(=NORa)NRaR , -alkylN(Rb)NRaRb, -alkylN(Rb)C(=O)Ra, -alkylN(R )C(=O)ORa, -alkylN(Rb)C(=O)NRaR ,
-alkylN(R )SO2NRaRb, -alkylN(Rb)SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaRb and R10a;
RiOa is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R10a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkyINH2, -alkylN(H)(alkyl), -alkylN(alkyl)2,
Figure imgf000095_0001
-alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
Rπ is alkyl, alkenyl, alkynyl, -C(=O)NRaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each Rπ is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb, -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaRb,
-N(R )SO2NRaRb, -C(=O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaR , -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaR , -C(alkyl)=NNRaRb, -C(H)(=NORa)NRaR , -C(alkyl)(=NORa)NRaRb, -alkylN(Rb)NRaRb, -alkylN(Rb)C(=O)Ra, -alkylN(R )C(=O)ORa, -alkylN(Rb)C(=O)NRaRb,
-alkylN(Rb)SO2NRaRb, -alkylN(R )SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaRb and Rlla;
Rπa is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each Rlla is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O) H2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
Ri2 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or cycloalkenylalkyl; wherein each Ri2 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, alkoxy cyano, nitro and halo;
R13 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R13 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb, -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N^SOzRa, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaRb, -N(Rb)SO2NRaRb, -C(=O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaR , -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(alkyl)=NNRaRb, -C(H)(=NORa)NRaRb, -C(alkyl)(=NORa)NRaRb, -alkylN(Rb)NRaR , -alkylN(Rb)C(=O)Ra, -alkylN(Rb)C(=O)ORa, -alkylN(R )C(=O)NRaR , -alkylN(Rb)SO2NRaR , -alkylN(Rb)SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaR and R13a; R13a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R13a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(-O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2; Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle; wherein each Ra and Rb, at each occurrence, is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and R,; alternatively, Ra and Rb, together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), ~SO2(alkyI), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH,
-C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Re;
Re is aryl, heteroaryl or heterocycle; wherein each Re is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)2, -alkyl-N(H)C(=O)NH2, -alkyl-N(H)C(=O)N(H)(alkyl), -alkyl-N(H)C(=O)N(alkyl)2, -alkyl-C(=O)OH, -alkyl-C(=O)Oalkyl, -alkyl-C(=O)NH2, -alkyl-C(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2; and n is 1 or 2. For example, the present invention provides a compound of formula (VII) wherein R\ is OH and R2 is H. For example, the present invention provides a compound of formula (Nil) wherein Ri is OH, R2 is H, X is O and Y is O. For example, the present invention provides a compound of formula (Nil) wherein wherein Ri is OH, 2 is H, X is O, Y is O and R3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra or -alkylΝRaR . For example, the present invention provides a compound of formula (Nil) wherein Ri is OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkylalkyl and R4 is aryl or heteroaryl. For example, the present invention provides a compound of formula (Nil) wherein Ri is OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkylalkyl and t is phenyl. For example, the present invention provides a compound of formula (Nil) wherein Ri is OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkylalkyl and 4 is phenyl substituted with
0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -ΝR4aR4 and -C(R4b)=NOR4a; wherein Rta and t are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (Nil) wherein Ri is OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkylalkyl, R4 is phenyl substituted with 0,
1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, - RtaRn, and -C(R4b)=ΝOR4a, and R is phenylmethyl; wherein R4a and tb are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (Nil) wherein Ri is OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkylalkyl, t is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -ΝR aR b and -C(R4b)=NOR4a, R is phenylmethyl and R7 is alkyl; wherein ta and tb are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of formula (Nil) wherein Ri is OH, R2 is H, R3 is C3, alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, R4 is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -N ta n, and -C(R b)=NOR4a, R is phenylmethyl and R7 is alkyl; wherein ta and R b are independently selected from the group consisting of hydrogen and alkyl. For example, the present invention provides a compound of foπnula (VII) wherein Ri is OH, R2 is H, R3 is C3, alkyl, C4 alkyl, C5 alkyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, t is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta,
Figure imgf000098_0001
R is phenylmethyl and R7 is CI alkyl, C2 alkyl, C3 allcyl, C4 alkyl or C5 alkyl; wherein Rta and R4 are independently selected from the group consisting of hydrogen and alkyl. In an eighth embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound, or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrag, or combination thereof, and a pharmaceutically acceptable carrier. In a ninth embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, one, two, three, five or six second HIV protease inhibitors, and a phaπnaceutically acceptable carrier. For example, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of ane ester, prodrug, salt of a prodrug, or combination thereof, one, two, three, four, five or six second HIV protease inhibitors selected from the group consisting of ritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir, nelfmavir, tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L- 756423, RO0334649, KNI-272, DPC-681, DPC-684 and GW640385X, and a pharmaceutically acceptable carrier. In a tenth embodiment the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, one, two, three, four, five or six HIV reverse transcriptase inhibitors, and a pharmaceutically acceptable carrier. For example, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound, or combination of compounds of formula (I), (II), (III), (IN), (N), (NI) or (Nil), or a phaπnaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, one, two, three, four, five or six HIV reverse transcriptase inhibitors selected from the group consisting of lamivudine, stavudine, zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (±-FTC), D-D4FC (Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz, capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC-083), DPC-961, MIV-150, TMC-120 and TMC- 125, and a pharmaceutically acceptable carrier. In an eleventh embodiment the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, one, two, three, four, five or six HIV entry/fusion inhibitors, and a pharmaceutically acceptable carrier. For example, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a phaπnaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, one, two, three, four, five or six HIV entry/fusion inhibitors selected from the group consisting of enfuvirtide (T-20), T-1249, PRO 2000, PRO 542, PRO 140, AMD-3100, BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D (SCH-D), TΝX-355 and UK- 427857, and a pharmaceutically acceptable carrier. In a twelfth embodiment the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, one, two, three, four, five or six HIV integrase inhibitors, and a pharmaceutically acceptable carrier. For example, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrag, or combination thereof, one, two, three or four HIV integrase inhibitors selected from the group consisting of S-1360, zintevir (AR-177), L-870812 and L-870810, and a pharmaceutically acceptable carrier. In a thirteenth embodiment the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of foπnula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrag, or combination thereof, one, two, three, four, five or six HIV budding/maturation inhibitors, and a pharmaceutically acceptable carrier. For example, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, PA- 457, and a pharmaceutically acceptable carrier. In a fourteenth embodiment the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrag, or combination thereof, one, two or three second HIV protease inhibitors, one, two or three HIV reverese transcriptase inhibitors, and a pharmaceutically acceptable carrier. For example, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, one, two or three second HIV protease inhibitors selected from the group consisting of ritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684 and GW640385X, one, two or three HIV reverse transcriptase inhibitors selected from the group consisting of lamivudine, stavudine, zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIV- 210, Racivir (±-FTC), D-D4FC (Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz, capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC-083), DPC-961, MIV-150, TMC-120 and TMC-125, and a pharmaceutically acceptable caπier. In a fifteenth embodiment the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, one, two or three second HIV protease inhibitors, one, two or three HIV entry/fusion inhibitors, and a pharmaceutically acceptable carrier. For example, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formulae (I), (II), (III), (IN), (N), (NI) or (Nil), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrag, or combination thereof, one, two or three second HIN protease inhibitors selected from the group consisting of ritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KΝI-272, DPC-681, DPC-684 and GW640385X, one, two or three HIN entry/fusion inhibitors selected from the group consisting of enfuvirtide (T-20), T-1249, PRO 2000, PRO 542, PRO 140, AMD-3100, BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D (SCH-D), TΝX-355 and UK-427857, and a pharmaceutically acceptable carrier. In a sixteenth embodiment the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IN), (N), (NI) or (Nil), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, one, two or three second HIN protease inhibitors, one, two or three HIN integrase inhibitors, and a pharmaceutically acceptable carrier. For example, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compoimd, or combination of compounds of formulae (I), (II), (III), (IN), (N), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrag, or combination thereof, one, two or three second HIV protease inhibitors selected from the group consisting of ritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KΝI-272, DPC-681, DPC-684 and GW640385X, one, two or three HIV integrase inhibitors selected from the group consisting of S-1360, zintevir (AR-177), L-870812 and L-870810, and a pharmaceutically acceptable carrier. In a seventeenth embodiment the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrag, or combination thereof, one, two or three second HIV protease inhibitors, one, two or three HIN budding/maturation inhibitors, and a pharmaceutically acceptable carrier. For example, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of formulae (I), (II), (III), (IN), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, one, two or three second HIV protease inhibitors selected from the group consisting of ritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684 and GW640385X, PA-457, and a pharmaceutically acceptable carrier. In an eighteenth embodiment, the present invention provides a method of inhibiting the replication of an HIV virus comprising contacting said virus with a therapeuctially effective amount of a compound or combination of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a phaπnaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrag, or combination thereof. In a ninteenth embodiment, the present invention provides a method of inhibiting the replication of HIV comprising contacting said virus with any one of the pharmaceutical composition as disclosed hereinabove. In a twentieth embodiment, the present invention provides a method of treating or preventing an HIV infection comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrag, or combination thereof. In a twenty-first embodiment the present invention provides a method of treating or preventing an HIV infection comprising administering to a patient in need of such treatment any one of the pharmaceutical composition as disclosed hereinabove. In a twenty-second embodiment the present invention provides a method of inhibiting an HIV protease comprising contacting said HIV protease with a therapeuctially effective amount of a compound or combination of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof. In a twenty-third embodiment the present invention provides a method of inhibiting an HIV protease comprising contacting said protease with any one of the pharmaceutical compositions as disclosed hereinabove. The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991). N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; sulfenyl groups such as phenylsulfenyl (phenyl-S-), triphenylmethylsulfenyl (trityl-S-) and the like; sulfinyl groups such as p- methylphenylsulfinyl (p-methylphenyl-S(O)-), t-butylsulfinyl (t-Bu-S(O)-) and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3 ,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)-l-methylethoxycarbonyl, dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloro-ethoxy-carbonyl, phenoxycarbonyl, 4-nitro- phenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyl- oxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl, benzyloxymethyl and the like; p-methoxyphenyl ' and the like; and silyl groups such as trimethylsilyl and the like. Prefened N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). As used herein, the terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30. The compounds of the invention can comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the invention substantially free from their enantiomers or other diastereomers. By "substantially free" is meant greater than about 80% free of other enantiomers or diastereomers of the compound, more preferably greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95% free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound. In addition, compounds comprising the possible geometric isomers of carbon-carbon double bonds and carbon-nitrogen double are also meant to be included in this invention. Individual stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill in the art. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers and then chromatographically separating the diastereomers and regeneration of the individual enantiomers, enzymatic resolution and the like. Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions which do not cause racemization or inversion of stereochemistry at the chiral centers. Diastereomeric mixtures of compounds resulting from a synthetic reaction can often be separated by chromatographic techniques which are well-known to those of ordinary skill in the art. Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC. Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliaries. The resulting diastereomers can then be separated by column chromatography. This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids or organosulfonic acids are especially useful as chiral auxiliaries. Once the diastereomers have been separated by chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be recovered and used again. Enzymes, such as esterases, phosphatases and lipases, can be useful for resolution of derivatives of the enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be prepared. Certain enzymes will selectively hydrolyze only one of the enantiomers in the mixture. Then the resulting enantiomerically pure acid can be separated from the unhydrolyzed ester. In addition, solvates and hydrates of the compounds of Formula (I), (II), (III), (IV), (V), (VI) or (VII), are meant to be included in this invention. When any variable (for example A, R, Rl5 R2, R3, Rt, R5, R6, R7, R8, R9, Rio, R11, R12, R13, R14, Ra, Rb, Re, n, etc.) occurs more than one time in any substituent or in the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or any other formula herein, its definition on each occuπence is independent of its definition at every other occuπence. In addition, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture. The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: 4- acetamido-benzoate, acetate, adipate, alginate, carbonate, 4-chlorobenzenesulfonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, cholate, digluconate, cyclopentanepropionate, dichloroacetate, dodecylsulfate, ethanedisulfonate, ethanesulfonate, ethylsuccinate, formate, fumarate, galactarate, D- gluconate, D-glucuronate, glucoheptanoate, glutarate, lycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate (isethionate), 3-hydroxy-2-naphthoate, l-hydroxy-2-naphthoate, lactate, lactobionate, laurate, maleate, malonate, mandelate, methanesulfonate, nicotinate, 1,5-naphthalene-disulfonate, 2-naphthalenesulfonate, oleate, oxalate, pamoate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, L-pyroglutamate, sebacate, stearate, succinate, tartrate, terephthalate, thiocyanate, p-toluenesulfonate, undecanoate, undecylenoate and valerate. Also, the basic nitrogen-containing groups can be quatemized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as aluminum, sodium, lithium, potassium, calcium, magnesium or zinc or with organic bases such as diethylethanolamine, diethanolamine, ethylenediamine, guanidine, meglumine, olamine (ethnolamine), piperazine, piperidine, triethylamine, tromethamine, benzathine, benzene- ethanamine, adenine, cytosine, diethylamine, glucosamine, guanine, nicotinamide, hydrabamine, tributylamine, deanol, epolamine or triethanolamine. Represenative salts of the compounds of the present invention include, but not limited to, hydrochloride, methanesulfonate, sulfonate, phosphonate, isethionate and trifluoroacetate. The compounds of the present invention can also be used in the form of prodrugs.
Examples of such prodrugs include compounds wherein one, two or three hydroxy groups in the compound of this invention are functionalized with R15 wherein R15 is
Figure imgf000105_0001
wherein
Ri03 is C(Ri05)2, O or -N(R105);
R10 is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl, each M is independently selected from the group consisting of H, Li, Na, K, Mg, Ca, Ba, -N(Ri05)2, alkyl, alkenyl, and R106; wherein 1 to 4-CH2 radicals of the alkyl or alkenyl, other than the -CH2 radical that is bound to Z, is optionally replaced by a heteroatom group selected from the group consisting of O, S, S(O), SO2 and N(R105); and wherein any hydrogen in said alkyl, alkenyl or R106 is optionally replaced with a substituent selected from the group consisting of oxo, -OR105, -R105, -N(R105)2, -CN, -C(O)OR105, -C(O)N(Rι05)2, -SO2N(Ri05), -N(Rio5)C(O)Ri05, -C(O)R105, -SR105, -S(O)R105, -SO2R105, -OCF3, -SR106, -SOR106, -SO2R106, -N(Ri05)SO2Rιo5, halo, -CF3 and NO2; Z is CH2, O, S, -N(R105), or, when M is absent, H; Q is O or S; W is P or S; wherein when W is S, Z is not S;
M' is H, alkyl, alkenyl or R106; wherein 1 to 4 -CH2 radicals of the alkyl or alkenyl is optionally replaced by a heteroatom group selected from O, S, S(O), SO2, or N(R105); and wherein any hydrogen in said alkyl, alkenyl or Rioe is optionally replaced with a substituent selected from the group consisting of oxo, -OR105, -R105, -N(Rιo5)2, -CN, -C(O)OR105, -C(O)N(R105)2, -SO2N(R105), -N(Rι05)C(O)Rio5, -C(O)R105, -SR105, -S(O)R105, -SO2R105, -OCF3, -SR106, -SORioe, -SO2Rι06, -N(Ri05)SO2Rιo5, halo, -CF3 andNO2; R106 is a monocyclic or bicyclic ring system selected from the group consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and heterocycle; wherein any of said heteroaryl and heterocycle ring systems contains one or more heteroatom selected from the group consisting of O, N, S, SO, SO2 and N(R105); and wherein any of said ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of hydroxy, alkyl, alkoxy, and -OC(O)alkyl; each R105 is independently selected from the group consisting of H or alkyl; wherein said alkyl is optionally substituted with a ring system selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocycle; wherein any of said heteroaryl and heterocycle ring systems contains one or more heteroatoms selected from the group consisting of O, N, S, SO, SO2, and N(Rios); and wherein any one of said ring system is substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of oxo, -OR105, -R105, -N(R105)2, -N(R105)C(O)Ri05, -CN, -C(O)OR105, -C(O)N(R105)2, halo and -CF3; q is O or l; m is 0 or 1; and t is 0 or 1. Representative examples of R15 of formula (VIII) or (IX) that can be utilized for the functionalization of the hydroxy groups in the compound of the present invention include, but not limited to, the following:
Figure imgf000107_0001
Figure imgf000107_0003
-(L)-lysine, -PO3Na2,
Figure imgf000107_0004
-(L)-tyrosin
Figure imgf000107_0002
, -PO3Mg,
-PO3(NH4)2 , -CH2-OPO3Na, -(L)-serine,
Figure imgf000107_0005
-SO3Na2,
Figure imgf000107_0006
-SO3Mg, -SO3(NH4)2,
-CH2-OSO3Na2 , -CH2-OSO3(NH4)2,
Figure imgf000107_0007
Figure imgf000107_0008
Figure imgf000107_0009
acetyl,
Figure imgf000107_0010
-(L)-valine,
-(L)-glutamic acid, -(L)-aspartic acid, -(L)-γ-tert-aspartic acid,
Figure imgf000107_0011
-(lL-(L)-3-pyridylalanine, -(L)-histidine, -CHO, -C(O)CF3>
Figure imgf000108_0001
It will be understood by those of skill in the art that component M or M' in the formulae set forth herein will have either a covalent, a covalent/zwitterionic, or an ionic association with either Z or R103 depending upon the actual choice for M or M'. When M or M' is hydrogen, alkyl, alkenyl or R106, then M or M', is covalently bound to -R103 or Z. If M is a mono or bivalent metal or other charged species (i.e. NH4 +), there is an ionic interaction between M and Z and the resulting compound is a salt. These prodrugs of the compoimd of the present invention serve to increase the solubility of these compounds in the gastrointestinal tract. These prodrags also serve to increase solubility for intravenous admimsfration of the compound. These prodrugs may be prepared by using conventional synthetic techniques. One of skill in the art would be well aware of conventional synthetic reagents to convert one or more of the hydroxy groups of the compounds of the present invention to a desired prodrug, functionalized by the substituents of formula (NIII) or (IX) as defined above. The prodrugs of this invention are metabolized in vivo to provide the compound of this invention. The compounds of the invention are useful for inliibiting retro viral protease, in particular HIN protease, in vitro or in vivo (especially in mammals and in particular in humans). The compounds of the present invention are also useful for the inhibition of retrovirases in vivo, especially human immunodeficiency virus (HIN). The compounds of the present invention are also useful for the treatment or prophylaxis of diseases caused by retrovirases, especially acquired immune deficiency syndrome or an HIN infection in a human or other mammal. Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 20 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drag combination, and the severity of the particular disease undergoing therapy. The compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal adminisfration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection, or infusion techniques. Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Suppositories for rectal administration of the drag can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drag. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syraps, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically aceptable and metabolizable lipid capabale of forming liposomes can be used. The present compositions in liposome form can contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients, and the like. The prefened lipids are the phospholipids and phosphatidyl cholines (lecithins), both natureal and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY. (1976), p. 33. While the compound of the invention can be administered as the sole active pharmaceutical agent, it can also be used in combination with one or more immimomodulators, antiviral agents, other antiinfective agents or vaccines. Other antiviral agents to be administered in combination with a compound of the present invention include AL-721, beta interferon, polymannoacetate, reverse transcriptase inhibitors (for example, BCH-189, AzdU, carbovir, ddA, d4C, d4T (stavudine), 3TC (lamivudine) DP-AZT, FLT (fluorothymidine), BCH-189, 5-halo-3'-thia- dideoxycytidine, PMEA, bis-POMPMEA, zidovudine (AZT), MSA-300, trovirdine, R82193, L-697,661, BI-RG-587 (nevirapine), abacavir, zalcitabine, didanosine, tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (±-FTC), D-D4FC (Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz, capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC- 083), DPC-961, MIV-150, TMC-120, and TMC-125 and the like), refroviral protease inhibitors (for example, HIV protease inhibitors such as ritonavir, lopinavir, saquinavir, amprenavir (VX-478), fosamprenavir, nelfinavir (AG1343), tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, SC-52151, BMS 186,318, SC-55389a, BILA 1096 BS, DMP-323, KNI-227, and the like), HEPT compounds, L,697,639, R82150, U- 87201E and the like), HIV integrase inhibitors (S-1360, zintevir (AR-177), L-870812 L- 870810 and the like), TAT inhibitors (for example, RO-24-7429 and the like), trisodium phosphonoformate, HPA-23, eflonithine, Peptide T, Reticulose (nucleophosphoprotein), ansamycin LM 427, trimetrexate, UA001, ribavirin, alpha interferon, oxetanocin, oxetanocin- G, cylobut-G, cyclobut-A, ara-M, BW882C87, foscamet, BW256U87, BW348U87, L- 693,989, BV ara-U, CMV triclonal antibodies, FIAC, HOE-602, HPMPC, MSL-109, TI-23, trifluridine, vidarabine, famciclovir, penciclovir, acyclovir, ganciclor, castanosperminem rCD4/CD4-IgG, CD4- PE40, butyl-DNJ, hypericin, oxamyristic acid, dextran sulfate and pentosan polysulfate. Other agents that can be administered in combination with the compound of the present invention include HIV entry/fusion inhibitor (enfuvirtide (T-20), T- 1249, PRO 2000, PRO 542, PRO 140, AMD-3100, BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D (SCH-D), TNX-355, UK-427857and the like) and HIV budding/maturation inhibitor such as PA-457. Immunomodulators that can be administered in combination with the compound of the present invention include bropirimine, Ampligen, anti-human alpha interferon antibody, colony stimulting factor, CL246,738, Imreg-1, Imreg- 2, diethydithiocarbamate, interleukin-2, alpha-interferon, inosine pranobex, methionine enkephalin, murarnyl-tripeptide, TP-5, erythropoietin, naltrexone, tumor necrosis factor, beta interferon, gamma interferon, interleukin-3, interleukin-4, autologous CD 8+ infusion, alpha interferon immunoglobulin, IGF-1, anti- Leu-3A, auto vaccination, biostimulation, extracorporeal photophoresis, cyclosporin, rapamycin, FK-565, FK-506, G-CSF, GM-CSF, hyperthermia, isopinosine, IVIG, HIVIG, passive immunotherapy and polio vaccine hyperimmunization. Other antiinfective agents that can be administered in combination with the compound of the present invention include pentamidine isethionate. Any of a variety of HIV or AIDS vaccines (for example, gρl20 (recombinant), Env 2-3 (gρl20), HIVAC-le (gpl20), gpl60 (recombinant), VaxSyn HIV-1 (gρl60), Immuno-Ag (gpl60), HGP-30, HIV- Immunogen, p24 (recombinant), VaxSyn HIV-1 (p24)) can be used in combination with the compound of the present invention. Other agents that can be used in combination with the compoimd of this invention are ansamycin LM 427, apurinic acid, ABPP, Al-721, carrisyn, AS-101, avarol, azimexon, colchicine, compound Q, CS-85, N- acetyl cysteine, (2-oxothiazolidine-4-carboxylate), D- pemcillamine, diphenylhydantoin, EL- 10, erythropoieten, flisidic acid, glucan, HPA-23, human growth hormone, hydroxchloroquine, iscador, L-ofloxacin or other quinolone antibiotics, lentinan, lithium carbonate, MM-1, monolaurin, MTP-PE, naltrexone, neurofropin, ozone, PAI, panax ginseng, pentofylline, pentoxifylline, Peptide T, pine cone extract, polymannoacetate, reticulose, retrogen, ribavirin, ribozymes, RS-47, Sdc-28, silicotungstate, THA, thymic humoral factor, thymopentin, thymosin fraction 5, thymosin alpha one, thymostimulin, UA001, uridine, vitamin B 12 and wobemugos. Other agents that can be used in combination with the compound of this invention are antifungals such as amphotericin B, clotrimazole, flucytosine, fluconazole, ifraconazole, ketoconazole and nystatin and the like. Other agents that can be used in combination with the compound of this invention are antibacterials such as amikacin sulfate, azithromycin, ciprofloxacin, tosufloxacin, clarithromycin, clofazimine, ethambutol, isoniazid, pyrazinamide, rifabutin, rifampin, streptomycin and TLC G-65 and the like. Other agents that can be used in combination with the compoimd of this invention are anti-neoplasties such as alpha interferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD (methotrexate, bleomycin, doxorabicin, cyclophosphamide, vincristine and dexamethasone), PRO-MACE/MOPP (prednisone, methotrexate (w/leucovin rescue), doxorabicin, cyclophosphamide, taxol, etoposide/mechlorethamine, vincristine, prednisone and procarbazine), vincristine, vinblastine, angioinhibins, pentosan polysulfate, platelet factor 4 and SP-PG and the like. Other agents that can be used in combination with the compound of this invention are drugs for treating neurological disease such as peptide T, ritalin, lithium, elavil, phenytoin, carbamazipine, mexitetine, heparin and cytosine arabinoside and the like. Other agents that can be used in combination with the compound of this invention are anti-protozoals such as albendazole, azithromycin, clarithromycin, clindamycin, corticosteroids, dapsone, DIMP, eflornithine, 566C80, fansidar, furazolidone, L,671,329, letrazuril, metronidazole, paromycin, pefloxacin, pentamidine, piritrexim, primaquine, pyrimethamine, somatostatin, spiramycin, sulfadiazine, trimethoprim, TMP/SMX, trimetrexate and WR 6026 and the like. For example, a compound of this invention can be administered in combination with ritonavir. Such a combination is especially useful for inhibiting HIV protease in a human. Such a combination is also especially useful for inhibiting or treating an HIV infection in a human. When used in such a combination the compound of this invention and ritonavir can be administered as separate agents at the same or different times or they can be formulated as a single composition comprising both compounds.
- I ll - When administered in combination with a compound, or combination of compounds of this invention, ritonavir causes an improvement in the pharmacokinetics (i.e., increases half-life, increases the time to peak plasma concentration, increases blood levels) of the compound of this invention. Another combination can comprise of a compound, or combination of compounds of the present invention with ritonavir and one or more reverse transcriptase inhibitors (for example, lamivudine, stavudine, zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (±-FTC), D-D4FC (Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz, capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC-083), DPC-961, MIV-150 TMC-120, TMC-125 and the like). Such a combination is useful for inhibiting or treating an HIV infection in a human. When used in such a combination the compound or combination of compounds of the present invention and ritonavir and one or more reverse transcriptase inhibitors can be administered as separate agents at the same or different times or they can be formulated as compositions comprising two or more of the compounds. It will be understood that agents which can be combined with the compound of the present invention for the inhibition, treatment or prophylaxis of AIDS or an HIV infection are not limited to those listed above, but include in principle any agents useful for the treatment or prophylaxis of AIDS or an HIV infection. When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition. The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.
Antiviral Activity Determination of Activity against wild-type HIV or the Passaged Variants MT4 cells were infected with 0.003 multiplicity of infection (MOI) of wild-type HIV-
1 or the passaged mutant variants at 1 X 10°" cells/mL for 1 h, washed twice to remove unabsorbed virus and resuspended to 1 X 105 cells/mL of medium, seeded in a 96-well plate at lOOμL/well, and treated with an equal volume of solution of inhibitor in a series of half log dilutions in RPMI 1640 (Rosewell Park Memorial Institute) media (Gibco) containing 10% fetal bovine serum (FBS), in triplicate. The final concentration of DMSO in all wells was 0.5%). The virus control culture was treated in an identical manner except no inhibitor was added to the medium. The cell control was incubated in the absence of inhibitor or virus. Plates were incubated for 5 days in a CO2 incubator at 37°C. On day 5, stock solution of 3- [4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) (4 mg/mL in PBS, Sigma cat. # M 5655) was added to each well at 25 μL per well. Plates were further incubated for 4 hrs, then treated with 20% sodium dodecyl sulfate (SDS) plus 0.02 N HCI at 50 μL per well to lyse the cells. After an overnight incubation, optical density (O.D.) was measured by reading the plates at 570/650 nm wavelengths on a Bio-Tek microtifre plate reader. Percent cytopathic effect (CPE) reduction was calculated from the formula below: ((O.D. test well - O.D. infected control well)/(O.D. uninfected control well - O.D. infected control well)) X 100 EC50 values were detennined from the plot of log (Fa/Fu) vs. log (compound concentration) using the median-effect equation (Chou, 1975, Proc. Int. Cong. Pharmacol. 6th p. 619) wherein Fa is the fraction inhibited by the compound, and Fu is the fraction uninhibited (1-Fa). When tested by the above method, the compounds of the present invention exhibit
EC50 in the range of InM to lOOnM.
Determination of anti-HIV Activity in the Presence of Human Serum The above antiviral assay was performed in 96-well tissue culture plates containing 50% human serum (HS) (Sigma) plus 10% FBS (Gibco/BRL, Grand Island, NY).
Compounds were dissolved in DMSO, diluted at half log concentrations in DMSO, then transfened to media without serum at four times the final concentration. These solutions were added to 96-well plates at 50 μL per well, in triplicate. Cells were separately infected with 0.003 MOI of HIV-1 at 1 X 10°" cells/mL for 1 h, washed twice to remove unadsorbed virus and resuspended to 2 X 105 cells/mL of media without serum. The cell suspension (50 μL) was seeded at 1 X 10^ cells per well. Uninfected cells were included as confrol. Final DMSO concenfration in all wells was 0.5% including uninfected and infected control wells. Cultures were incubated for 5 days in a CO2 incubator at 37°C. EC50 values were measured using MTT uptake as described above. When tested by the above method, compounds of the present invention exhibit EC50 in the range of 10 nM to 1 μM.
Generation of HIV-1 Resistant to ABT-378/r (A17) by In Vitro Passage MT4 cells (2xl06) were infected with pNL4-3 at an MOI of 0.03 for 2 h, washed, then cultured in the presence of ABT-378 and ritonavir at concentration ratio of 5: 1. The concenfration of ABT-378 and ritonavir used in the initial passage was 1 nM and 0.2 nM respectively. Viral replication was monitored by determination of p24 antigen levels in the culture supernatant (Abbott Laboratories), as well as by observation for any cytopathic effect (CPE) present in the cultures. When p24 antigen levels were positive, the viral supernatant was harvested for the proceeding passage. Following each passage, the drug concentrations in the subsequent passage were gradually increased. After 5 months of selection, 1.5 μM of ABT-378 can be used in the final passage. The A17 virus was generated after 17 passages of pNL4-3 in the presence of ABT-378 and ritonavir at concentration ratio of 5:1. When tested by the above method, compounds of the present invention exhibit EC50 in the range of InM to lμM.
Synthetic methods Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: DMF is N,N-dimethylformamide, DMSO is dimethylsulfoxide, THF is tetrahydrofuran, NMMO is 4-methylmorpholine N-oxide, HOBT is 1- hydroxybenzotriazole hydrate, DCC is 1,3-dicyclohexylcarbodiimide, EDAC is l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, DMAP is 4- (dimethylamino)pyridine, TFA is trifluoroacetic acid, and DEPBT is 3- (diethoxyphosphoryloxy)-l,2,3-benzotriazin-4(3H)-one. The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared. Starting materials can be obtained from commercial sources or prepared by well-established literature methods known to those of ordinary skill in the art. The groups A, R, R1} R2, R3, R , R5, R6, R7, R8, R9, R10, Rπ, R12, R13, R14 and n are as defined above unless otherwise noted below. This invention is intended to encompass compounds having formula (I), (II), (III), (IV), (V), (VI) or (VII) when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro. Compounds of the invention can be prepared according to the methods described in Schemes 1-5 as shown below.
Scheme 1
Figure imgf000116_0001
TFA
Figure imgf000116_0002
Compounds of formula (1) wherein Pi is an N-protecting group (for example tert- butyloxycarbonyl or benzyloxycarbonyl), can be treated with an amine having formula R3NH (for example isobutylamme, cyclopentymethylamme, cyclobutylmethylamine, and the like) in an alcoholic solvent such as, but not limited to, ethanol or methanol at a temperature of about 25°C to about 80°C, to give, compounds of the formula (2). Compounds of foπnula (2) can be deprotected with an acid (for example, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, aluminum chloride and the like) in an inert solvent (for example, dioxane, dichloromethane, chloroform, methanol, tetrahydrofuran, acetonitrile and the like) at a temperature from about 0°C to about room temperature, to provide (3). Treatment of compound (2) with sulfonyl chlorides of formula (4), such as, but not limited to, 4-methoxybenzenesulfonyl chloride in the presence of an organic amine base (for example, triethylamine, diisobutylethyl amine, pyridine, and the like), at a temperature of about 25°C to about 80°C, in an inert solvent such as, but not limited to, dichloromethane, diethyl ether, tetrahydrofuran, chloroform, N,N-dimethylformamide, and the like, or mixtures thereof, give compounds of formula (5). Compounds of formula (5) can be deprotected to compounds of formula (6) using the conditions for the transformation of (2) to (3). Compounds of formula (6) wherein ILt is 4-[hydroxyimino)methyl]phenyl can be obtained by (a) treating compounds of formula (2) with 4-(diacetoxymethyl)benzenesulfonyl chloride (7), (b) freating the product from step (a) with hydroxylamine, and (c) deprotection of the conesponding oxime of foπnula (8). Alternatively, compounds of formula (6) wherein t is 4- [hydroxyimino)methyl]phenyl can also be obtained by (a) freating compounds of formula (2) with 4-vinylbenzenesulfonyl chloride, (b) oxidation of the product of step (a) with an oxidizing agent such as, but not limited to, osmium tetroxide, in the presence of sodium metaperiodate to give aldehydes of formula (10), (c) treating compounds of formula (10) with hydroxylamine to give compounds of formula (8), and (d) deprotection of compounds of formula (8).
Scheme 2
Figure imgf000117_0001
16 17 Amino acid esters of formula (11), wherein P2 is lower alkyls (for example methyl, ethyl, tert-butyl and the like), can be treated with a suitably protected aldehyde of formula (12) (for example, Pι0 and Pn together with the nifrogen atom they are attached, form a phthahmido group) in the presence of a reducing agent under acidic conditions (for example, in the presence of acetic acid or hydrochloric acid) in an inert solvent, or mixture of solvents, such as methyl sulfoxide, methanol, dichloromethane, and the like, at a temperature of about room temperature to about 50°C, to provide compounds of formula (13). ι Examples of the reducing agent include, but are not limited to, sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydri.de, and BH3-pyridine. Removal of the phthahmido group can be achieved using hydrazine in a suitable solvent such as ethanol and the like, at a temperature of about room temperature to about 100°C, to provide compounds of formula (14). Compounds of formula (14) can be converted to compounds of formula (15) by (a) treating compounds of formula (14) with an aldehyde having formula R9CHO, optionally in the presence of a drying agent (for example, magnesium sulfate, silica gel and the like) in an inert solvent, or mixture of solvents, such as dichloromethane, benzene, toluene, methanol, ethanol, methyl sulfoxide, and the like, at a temperature from about room temperature to about 100°C, and (b) reacting the product of step (a) with a reducing agent at about room temperature. Examples of the reducing agent include, but are not limited to, sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, and BH3-pyridine. The diamine of formula (15) can be treated with a carbonylating agent in an inert , solvent, or mixture of solvents, such as dichloromethane, 1,2 dichloroethane, toluene, acetonitrile, and the like, at a temperature of about room temperature to about 100°C, to provide compounds of formula (16). Examples of the carbonylating agent include, but not are limited to, 4-nitrophenyl carbonate, phosphene, diphosgene, triphosgene, carbonyl diimidazole, disuccinimidyl carbonate. Conversion of compounds of formula (16) to the conesponding acids having formula (17) can be achieved by acid hydrolysis (for example acetic acid, trifluoroacetic acid, toluenesulfonic acid, formic acid, hydrochloric acid and the like) or base hydrolysis (for example sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, and the like) in a solvent, or mixture of solvents such as N,N-dimethylformamide, toluene, benzene, dichloromethane, ethyl acetate, water, methanol and the like, at a temperature of about 0°C to about 100°C.
Scheme 3
Figure imgf000119_0001
19 Ril X 21
Figure imgf000119_0002
Amino acid esters having formula (11), wherein P2 is lower alkyls (for example, methyl, ethyl, tert-butyl and the like) can be treated with compounds of formula R30OC(O)CH2X, wherein R30 is lower alkyls and X is Br, CI, or I, in an inert solvent, or mixture of solvents, such as N,N-dimethylformamide, dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, benzene, diethyl ether and the like, at a temperature of about room temperature to about 50°C, to provide (18). Compounds of formula (18) can be converted to compounds of foπnula (19) by (a) treating with chlorosulfonyl isocyanate (or compounds of formula XSO2NCO, wherein X is Br, CI, or I, and the like) in an inert solvent, or mixture of solvents, such as dichloromethane, 1,2-dichloroethane, dioxane, toluene, N,N-dimethylformamide, tetrahydrofuran diethyl ether and the like, at a temperature of about -10°C to about room temperature, and (b) treating the product of step (a) with water at about room temperature. Alternatively, (18) can be reacted with a carbonylating agent such as, but not are limited to, 4-nitrophenyl carbonate, phosphene, diphosgene, triphosgene, carbonyl diimidazole, disuccinimidyl carbonate, followed by reaction with ammonia. Cyclization of the compounds of formula (19) to provide compounds of formula (20) can be achieved be freating with an organic amine base such as triethyl amine, diisopropylethyl amine, imidazole, pyridine, N-methylmorpholine and the like, or an inorganic base such as sodium bicarbonate, sodium carbonate, cesium carbonate and the like, in an inert solvent, or mixture of solvents, such as methanol, ethanol, N,N- dimethylformamide, dioxane, xylene, tefrahydrofuran and the like, at a temperature of about room temperature to about 70°C. Imides of formula (20) can be converted to compounds of formula (22) by (a) deprotonation with a base in an inert solvent, or mixture of solvents, such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, and the like, at a temperature of about -78 to about 0°C, and (b) treating product of step (a) with an alkyl halide of formula (21), wherein X is CI, Br or I, at a temperature of about room temperature to about 100°C. Examples of the base include, but are not limited to, sodium hydride, potassium hydride, lithium diisopropyl amide, lithium bis(trimethylsilyl)amide. Alternatively, compounds of formula (20) can be converted to compounds of formula
(22) by treating with an alcohol having formula Ri iCH2OH, in the presence of triphenylphosphine and diethyl azodicarboxylate, in an inert solvent such as dichloromethane, tetrahydrofuran, dioxane or N,N-dimethylformamide, at a temperature of about 0°C to about 25°C. Conversion of compounds of formula (22) can be converted to compounds of formula
(23) using the conditions for the transformation of compounds of formula (16) to compounds of formula (17).
Scheme 4
Figure imgf000120_0001
21 26
Figure imgf000120_0002
Amino acid esters having formula (11) wherein P2 is lower alkyls (for example, methyl, ethyl, tert-butyl and the like) can be treated with compounds such as, but not limited to, bis-(4-nifrophenyl)carbonate in an inert solvent, or mixture of solvents, such as N,N- dimethylformamide, dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, benzene, diethyl ether and the like at a temperature of about room temperature to about 50 °C, to provide (24). Treatment of alkyl halides of formula (21) wherein X is CI, Br or I, with an amine of formula R12NH2 at a temperature of about 0°C to about 50°C in an open container or in a sealed vessel gives compounds of formula (26). Compounds of formula (26) is treated with (24) in an inert solvent, or mixture of solvents, such as N,N-dimethylformamide, dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, benzene, diethyl ether, and the like, at a temperature of about room temperature to about 100°C, to provide compounds of formula (27). Conversion of compounds of formula (27) to compounds of formula (28) can be achieved by using the conditions for the transformation of compounds of formula (16) to compounds of formula (17).
Scheme 5
Figure imgf000121_0001
Figure imgf000121_0002
Compounds of formula (6) V can be reacted with carbox Xylic acids of^ formula(17) (23), or the conesponding salts, and an activating agent, optionally in the presence of 1- hydroxy-7-azabenzotriazole (HO AT), 1-hydroxybenzotriazole hydrate (HOBT) or 3- hydroxy-l,2,3-benzotriazin-4(3H)-one (HOOBT), and optionally in the presence of an inorganic base (for example, NaHCO3, Na2CO3, KHCO3, K2CO3, NaOH or KOH, and the like) in an inert solvent (for example, 1 : 1 ethyl acetate/water or isopropyl acetate/water or toluene/water or tetrahydrofuran/water and the like) at about room temperature, or an organic amine base (for example, imidazole, 1-methylimidazole, 2-methylimidazole, 2- isopropylimidazole, 4-methylimidazole, 4-nitroimidazole, pyridine, N,N- dimethylaminopyridine, 1,2,4-triazole, pynole, 3-methylpynole, triethylamine orN- methylmorpholine and the like) in an inert solvent (for example, ethyl acetate, isopropyl acetate, tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide, dichloromethane and the like) at a temperature of about 0°C to about 50°C to provide compounds of formula (30). Examples of the activating agent include, but are not limited to, l,r-carbonyldiimidazole (CDI), l,3-dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC), DEPBT (3- (diethoxyphosphoryloxy)-l,2,3-benzotriazin-4(3H)-one), PyBOP (benzotriazole- 1-yl-oxy- tris-pynolidinophosphonium hexafluorophosphate), and 1,3-di-tert-butylcarbodiimide. Alternatively, a salt or an activated ester derivative of acid (17) or (23) (for example, the acid chloride, prepared by reaction of the carboxylic acid with thionyl chloride in ethyl acetate or tefrahydrofuran or oxalyl chloride in toluene/N,N-dimethylformamide) can be reacted with (6). Alternatively, compounds of formula (30) can be obtained by (a) treating compounds of formula (3) with compounds of formula (17) using the conditions for the transformation of compound of formula (6) to (30), and (b) treating the product from step (a) with a compound having foπnula R SO2Cl, using the conditions for the transformation of compounds of formula (2) to compounds of formula (5). Compounds of formula (6) can also be coupled to acids having formula (28) using the coupling conditions for the transformation of compounds of formula (6) to (30). The present invention will now be described in connection with certain prefened embodiments which are not intended to limit its scope. On the contrary, the present invention covers all alternatives, modifications, and equivalents as can be included within the scope of the claims. Thus, the following examples, which include prefened embodiments, will illustrate the prefened practice of the present invention, it being understood that the examples are for the purpose of illustration of certain prefened embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects. It will be understood that the term "purification" used hereinafter, unless otherwise stated, means column chromatography using a silica gel column and eluting the column with a solvent system as specified in the experimental details. Compounds of the invention were named by ACD/ChemSketch version 4.01 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or were given names consistent with ACD nomenclature.
Example 1 tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate To a solution of (2R,3S)-3-N-tert-butoxycarbonylamino-l,2-epoxy-4-phenylbutane
(10 g) in 2-propanol (100 mL) was added isobutylamme (11.4 mL, 3 equivalents), and the mixture was heated at 80°C for 2.5 hours. After evaporation of the solvents, 11.86 g (93%) of the amine was produced in pure enough form for use in the next step. 1H NMR (300 MHz,
CDC13) δ ppm 0.90 (d, J=1.47 Hz, 3H), 0.92 (d, J=1.47 Hz, 3H), 1.35 (s, 9H), 1.59 (s, IH), 1.70 (m, IH), 2.41 (d, J=6.99 Hz, 2H), 2.68 (d, J=4.78 Hz, 2H), 2.88 (d, J=8.09 Hz, IH), 2.97
(d, J=4.41Hz, IH), 3.01 (d, J=4.78 Hz, IH), 3.45 (q, J=5.52Hz, IH), 3.80 (s, IH), 4.68 (d,
J=8.09 Hz, IH), 7.21 (m, 3H), 7.29 (m, 2H). The compounds listed in Table 1, wherein X3 represents the point of attachment to the core structure A , were repared by the procedure of Exam le 1.
Figure imgf000123_0001
Example 16 tert-butyl (1 S,2R 1 -benzyl-2-hydroxy-3- {isobutyl[(4- vinylphenyl)sulfonyl]amino}propylcarbamate To a solution of Example 1 (11.86 g) in dichloromethane (100 mL) was added triethylamine (TEA) (19.6 mL, 4 equivalents) followed by dropwise addition of vinylbenzenesulfonyl chloride (8.36 g, 1.2 equivalents) at 25°C for 3 hrs. The mixture was partitioned in IN sodium bicarbonate (NaHCO3) and ethyl acetate (EtOAc). The organic extract was concentrated, and the residue was chromatographed on silica gel, eluting with ethyl acetate /hexanes (1 :4) to afford the title compound (9.6 g, 54%). 1H NMR (300 MHz, CDC13): δ ppm 0.87 (d, J=6.44 Hz, 3H), 0.90 (d, J=6.78 Hz, 3H), 1.34 (s, 9H), 1.86 (m, IH), 2.84 (dd, J=13.39, 6.61 Hz, 2H), 2.97 (m, 3H), 3.11 (m, 3H), 3.79 (s, IH), 4.61 (s, IH), 5.44 (d, J=10.85 Hz, IH), 5.88 (d, J=17.63 Hz, IH), 6.75 (dd, J=17.63, 10.85 Hz, IH), 7.25 (m, 5 H), 7.51 (d, J=8.48 Hz, 2H), 7.72 (d, J=8.48 Hz, 2H).
Example 17 ■ tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-[({4- [hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate Method A Part i tert-butyl ( 1 S,2R)- 1 -benzyl-3 - [ [(4-formylphenyl)sulfonyl] (isobutyl)amino] -2- hydroxypropylcarbamate To Example 16 (8 g) in 80% tetrahydrofuran/water (120 mL) at 25°C was added OsO solution (2.9 mL, 4% by weight in water) followed by sodium periodate (6.76 g, 2 equivalents). The mixture was stined at 25°C for 16 hrs, quenched with 10% sodium thiosulfate solution, and extracted with ethyl acetate. The organic extract was concentrated, and the residue was chromatographed on silica gel, eluting with 3% methanol/dichloromethane to give the title compound (7 g, 87%). Part 2 tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-[({4- [(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate A solution of hydroxylamine hydrochloride (2.08 g) in methanol (20 mL) was treated with a solution of KOH (1.68 g, 1 equivalent) in methanol (10 mL) at 0°C, stined for 30 min, and filtered to give a 1 M solution of hydroxylamine. This solution (15 mL, 1.5 equivalents) was added to a solution of the product of Part 1 of method A (7 g) in methanol (25 mL) at 25°C and stined for 1 h. The reaction mixture was partitioned between ethyl acetate and brine. The organic exfract was concentrated. The residue was chromatographed on silica gel using 5% methanol/CHCl3. A second purification was performed using 15% ethyl acetate in dichloromethane to give the product (6.85 g, 95%). Method B Part i
(acetyloxy) [4-(chlorosulfonyl)phenyl]methyl acetate A solution of p-toluenesulfonyl chloride (40.2 g) in acetic acid: acetic anhydride (800 mL, 1:1) was treated with cone, sulfuric acid (64 mL, 5 equivalents) at 0-5°C. Chromium trioxide (80 g, 4 equivalents) was added at such a rate that the temperature remained below 10 °C. The mixture was stined at 5-10°C until reaction was completed as indicated by TLC. The mixture was quenched with ice water (2 L), and the solids were filtered, washed with water, and dried. The solids were combined with saturated NaHCO3 (1 L) at 25°C for 2 hrs, filtered, dissolved in dichloromethane (1 L), dried over Na2SO4, filtered and concentrated. The residue was recrystallized from 2-3 volumes of hot acetone/pentane and cooling for 16 hrs. The crystals are filtered, and washed with cold pentane to give the product (24 g, 38%). 1H NMR (CDC13): δ 8.09 (d, J = 9 Hz, 2H), 7.77 (d, J = 9 Hz, 2H), 7.73 (s, IH), 2.16 (s, 6 H). Part 2 / (acetyloxy)(4-{[{(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4- phenylbutyl} (isobutyl)amino]sulfonyl}phenyl)methyl acetate A solution of Example 1 (12.82 g) in tetrahydrofuran (95 mL) was treated with triethylamine (15.9 mL), followed by a solution of the product of Part 1 of method B (14.0 g) in tetrahydrofuran (95 mL) and stined at 25°C for 4 hrs. The mixture was treated with saturated NaHCO3 solution (125 mL), and the solvents were evaporated. The residue was diluted with water and extracted with ethyl acetate (3 x), and the combined organic layers were dried over Na2SO4, filtered and concentrated to give the product. Part 3 tert-butyl (1 S,2R)- 1 -benzyl-2-hydroxy-3-[( {4- [hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate A solution of the product of Part 2 of method B (23.1 g) in ethanol (254 mL) was treated sequentially with hydroxylamine hydrochloride (5.29 g) and triethylamine (21.2 mL), stined at 75°C for 4 hrs, cooled to 25°C, and concentrated. The residue was diluted with ethyl acetate and washed sequentially with water (3 x) and saturated NaCl solution. The organic layer was separated, and concentrated. The solids formed was recrystallized by addition of about 2-3 volumes (relative to solid) of boiling ethyl acetate, followed by hexanes (2-3 volumes relative to ethyl acetate) until crystallization began. The mixture was kept at 25°C for 18 h, and the solids were filtered and washed with hexanes to give the product (14.38 g, 73%). Η NMR (300 MHz, CDC13) δ ppm 0.86 (d, J=6.44 Hz, 3H), 0.89 (d, J=6.78 Hz, 3H), 1.35 (s, 9H), 1.85 (m, IH), 2.95 (m, 2H), 2.94 (s, IH), 3.13 (m, 2H), 3.80 (s, 2H), 3.87 (s, IH), 4.63 (d, J=5.76 Hz, IH), 7.25 (m, 5H), 7.70 (d, J=8.48 Hz, 2H), 7.78 (d, J=8.48 Hz, 2H), 8.16 (s, IH). Example 18 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-[(E)-(hydroxyimino)methyl]-N- isobutylbenzenesulfonamide A solution of Example 17 in dichloromethane (60 mL) was treated with 80% trifluoroacetic acid at 0°C for 3 h. The solvents were evaporated, and the cis and trans oximes were treated with 5% trifluoroacetic acid in dichloromethane (20 mL) at 25 °C for 16 h. The solvents were evaporated, and the residue was partitioned between ethyl acetate and IN NaHCO3. After evaporating the solvents, the residue was filtered through a silica gel plug using 5% methanol in ethyl acetate (1% NH OH) and re-evaporated to give 3.62 g (91%). The trans isomer was separated from the cis by repeatedly crystallizing the solids from 5% methanol in ethyl acetate (50 mL). Approximately 3 g of pure trans isomer was recovered after six recrystalizations. The compounds listed in Table 2 wherein X3 represents the point of attachment to the core structure (B) were prepared by method A or method B as exemplified in Example 17 and Examplelδ.
Figure imgf000126_0001
(B)
Table 2
Figure imgf000126_0002
Figure imgf000127_0001
Example 32 (2S,3S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-l-imidazolidinyl}pentanoic acid
Example 32 A (l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)acetaldehyde To a solution of phthalimide diethylacetal (15 g) in tetrahydrofuran (THF) (30 mL) was added 10%) aqueous HCI (18 mL). After heating at 75 °C for 5 hrs, the solution was allowed to cool to RT, and ethyl acetate (100 mL) was added. The solution was extracted with saturated sodium carbonate solution (100 mL), brine (100 mL), and the organic layer was separated and dried over magnesium sulfate (MgSO4). The solution was filtered and evaporated to provide 11.2 g of the titled compound. Example 32B tert-butyl (2S,3 S)-2- { [2-( 1 ,3-dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)ethyl] amino } -3- methylpentanoate To a solution of Example 32A (12.1 g) in methanol (20 mL) was added L-isoleucine tert-butyl ester hydrochloride (13.0 g, 58 mmol), sodium cyanoborohydride (7.3 g, 116 mmol), and acetic acid (2mL). The resulting solution was stined for 3 hrs at 25°C and the methanol removed under vacuum, dichloromethane (500 mL) added, and the solution extracted with aq. NaHCO (2 x 300 mL). Evaporation and purification of the organic layer gave 12.9 g of the title compound.
Example 32C tert-butyl (2S,3S)-2-[(2-aminoethyl)amino]-3-methylpentanoate To a solution of Example 32B (12.9 g) in ethanol (400 mL) was added hydrazine hydrate (11.2 mL). The solution was then heated to 70°C for 2 hrs. After cooling to 25°C, the resulting solid was dissolved in IN NaOH solution (200 mL) and water (200 mL). The solution was then extracted with dichloromethane (3 x 200 mL), the organic exfracts combined, dried and evaporated to provide 6.8g of the title compound.
Example 32D tert-butyl (2S,3S)-3-methyl-2-[(2-{[(6-methyl-2- pyridinyl)methyl]amino}ethyl)amino]pentanoate 6-Methyl-2-pyridinecarboxaldehyde (4.25 g) was dissolved in dichloromethane (80 mL) and combined with Example 32C (8 g, 1 equivalent) and MgSO4 (15 g), and the mixture was stined at 25°C for 2.5 hrs. The mixture wais filtered, rinsed with dichloromethane, and the solvents were evaporated. The residue was dissolved in methanol (80 mL) and treated with NaBH4 at 0°C for 0.5 h. The solvents were evaporated, and the residue was partitioned between saturated NaHCO3 and ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, and the solvents were evaporated to give 11 g of the title compound.
Example 32E tert-butyl (2S,3S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-l- imidazolidinyl}pentanoate A solution of the product of Example 32D in N,N-dimethylformamide (60 mL) was treated with bis-(p-nitrophenyl) carbonate (12.6 g, 1.2 equivalents) at 50°C for 5 hrs. The solvents were evaporated, and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and the solvents were evaporated, and the residue was purified using ethyl acetate: hexanes (2:1) to give 7.3 g (57%>) of the title compound.
Example 32F (2S,3S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-l-imidazolidinyl}pentanoic acid A solution of the product of Example 32E (7.3 g) in dichloromethane (50 mL) and trifluoroacetic acid (50 mL) and the mixture was stined at 25°C for 3.5 hrs. The solvents were evaporated and the crude acid was used directly without purification. The compounds listed in Table 3, wherein X7 and X9 represents the points of connection to the core structure (C), were prepared by the procedures as exemplified in Examples 32A-32F, substituting the conesponding aldehydes to 6-methyl-2- pyridinecarboxaldehyde, and substituting the conesponding amino acid esters or the salts of the amino acid esters for L-isoleucine tert-butyl ester hydrochloride.
Figure imgf000129_0001
(C) Table 3
Figure imgf000129_0002
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Example 143 (2S)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxoimidazolidin-l-yl}butanoic acid
Example 143 A 2- { [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] amino } ethanol 2-Methyl-4-(chloromethyl)thiazole (2.24 g) was treated with ethanolamine (11.6 mL, 10 equivalents) in dichloromethane at 25°C for 16 hrs. The solvent was evaporated and the residue partitioned between ethyl acetate and brine. The organic layer was separated and exfracted with ethyl acetate (5x). The organic layers were combined and washed with brine, dried over Na2SO4, and the solvents were evaporated to give 2.4 g (85%) of title compound. Example 143B tert-butyl 2-hydroxyethyl[(2-methyl-l,3-thiazol-4-yl)methyl]carbamate The product of Example 143A (2.4 g) was treated with di-t-butyl dicarbonate (2.85 g, 1 equivalent) in tefrahydrofuran/ IM NaHCO3 (2:1) and stined at 25°C for 16 hrs. The solvents were evaporated, and the residue was acidified with 10% citric acid and exfracted with ethyl acetate (3x). The combined organic layer was washed with brine, dried over Na2SO4 and evaporated. The crude product was purified using 1%> methanol/dichloromethane to give 1.91 g (52%) of title compound.
Example 143C methyl (2S)-3-methyl-2-[(2-{[(2-methyl-l,3-thiazol-4- yl)methyl]amino}ethyl)amino]butanoate A solution of the product of Example 143B (2.26 g) in dichloromethane (20 mL) was treated with oxalyl chloride (5.4 mL, 1.5 equivalents) at -78°C, and stined for 15 min. DMSO (1.02 mL, 2 equivalents) was added dropwise at -78°C, stined for 15 min, and quenched with triethylamine (4 mL, 4 equivalents) as the mixture warmed to 0°C. The mixture was quenched with 20%) KH2PO4, and partitioned between dichloromethane and water. The organic layer was washed with brine, dried over Na2SO4, filtered, and the solvents were evaporated. To this crade product was added methanol/water (7:2), (L)-valine methyl ester (1.21 g, 1 equivalent), sodium acetate trihydrate (1.96 g, 2 equivalents), and NaCNBH3 (0.95 g, 2 equivalents) was added portionwise over 30 min. After stirring for 1 hour the mixture was partitioned between saturated NaHCO3 and extracted with ethyl acetate (2x). The combined organic layer was washed with brine, dried with Na2SO4, and evaporated. The residue was treated with dichloromethane/trifluoacetic acid (10 mL, 1 : 1) and stined at 25°C for 2 hrs and concentrated. Example 143D (2 S)-3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl} butanoic acid A solution of the product of Example 143C (5.4 g) in tetrahydrofuran (80 mL) was treated with carbonydiimidazole (6.1 g, 2 equivalents) at 25°C for 2 hrs. The mixture was quenched with 10% citric acid, the organic layer was separated, washed with water, brine, dried over Na2SO , filtered, and the solvents were evaporated A solution of the residue (3.3 g) in dioxane (20 mL) was treated with IM LiOH (20 mL) at 25°C for 2 hrs. The solvents were evaporated, and the residue was acidified with 10% HCI, extracted with dichloromethane/2-propanol (3:1), the organic layer was separated, dried over Na2SO4, filtered, and the solvents evaporated to give 1.5 g of the title compound. The compounds listed in Table 4, wherein X7 and X9 represents the points of connection to the core structure (C), were prepared by the procedures as exemplified in Examples 143A-143D, substituting the conesponding halides for 2-methyl-4- (chloromethyl)thiazole, and substituting the conesponding amino acid esters for (L)-valine methyl ester. Table 4
Figure imgf000135_0001
Figure imgf000136_0001
Example 148 (2S)-3 ,3-dimethyl-2- {3 - [( 1 -methyl- lH-benzimidazol-2-yl)methyl] -2-oxoimidazolidin- 1 - yl}butanoic acid
Example 148 A N-(2,2-dimethoxyethyl)-N-[(l-methyl-lH-benzimidazol-2-yl)methyl]amine A solution of l-methyl-2-formylbenzimidazole (lg) in methanol (27 mL) and acetic acid (0.54 mL) was treated with aminoacetaldehyde diethylacetal (0.9 g, 1 equivalent) and NaCNBH3 (0.85 g, 2 equivalents) at 25°C, stined for 1 hour. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed sequentially with saturated NaHCO3 and brine, and concentrated. The residue was chromatographed on silica gel, eluting with 8% methanol/dichloromethane to give 1.2 g (64%) of the title compound. ■ Example 148B 9H-fluoren-9-ylmethyl 2,2-dimethoxyethyl[(l-methyl-lH-benzimidazol-2- yl)methyl]carbamate A solution of the product of Example 148 A (1.2 g) in dichloromethane (30 mL) was treated with 9-fluorenylmethyl succinimide (1.6 g, 1.05 equivalents) at 0°C for 16 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed sequentially with 10%> NaHCO and brine, dried over Na SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with ethyl acetate: dichloromethane (1:1) to give 1.83 g (84%) of the title compound.
Example 148C 9H-fluoren-9-ylmethyl (l-methyl-lH-benzimidazol-2-yl)methyl(2-oxoethyl)carbamate A solution of the product of Example 148B (0.2 g) in tetrahydrofuran (0.2 mL) was treated with 30% HCI (0.2 mL), stined at 75°C for 6 hours, cooled to 25°C and concentrated. The residue was partitioned between 10% NaHCO3 and ethyl acetate, the organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound (175 mg).
Example 148D methyl (2S)-2-[(2- { [(9H-fluoren-9-ylmethoxy)carbonyl] [( 1 -methyl- 1 H-benzimidazol-2- yl)methyl]amino}ethyl)amino]-3,3-dimethylbutanoate A solution of the product of Example 148C (0.178 g) and (L)-methyl t-leucinate hydrochloride (76.1 mg, 1 equivalent) in methanol (1.7 mL) and acetic acid (17 μL) was treated with NaCNBH3 (54 mg, 2 equivalents) at 25°C for 3.5 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was separated and washed with IN NaHCO and brine, and concenfrated. The residue was chromatographed on silica gel, eluting with ethyl acetate: dichloromethane (3:1) to give 0.19 g (83%) of the title compound.
Example 148E methyl (2S)-3,3-dimethyl-2-{3-[(l-methyl-lH-benzimidazol-2-yl)methyl]-2- oxoimidazolidin-l-yl}butanoate A solution of the product of Example 148D (0.19 g) in N,N-dimethylformamide (3.5 mL) was freated with diethylamine (0.35 mL), stined at 25°C for 1.5 hours and concentrated. A solution of the residue in dichloroethane (7 mL) was treated with bis-(p-nifrophenyl) carbonate (0.128 g, 1.2 equivalents), stined at 60°C for 16 hours and concenfrated. The residue was chromatographed on silica gel, eluting with ethyl acetate: dichloromethane (3:2) to give 80 mg (64%) of the title compound.
Example 148F (2S)-3 ,3-dimethyl-2- {3- [( 1 -methyl- 1 H-benzimidazol-2-yl)methyl]-2-oxoimidazolidin- 1 - yl}butanoic acid A solution of the product of Example 148E (37 mg) in tetrahydrofuran (0.26 mL) and water (0.13 mL) was treated with LiOH (6.1 mg, 1.4 equivalents), stined at 25°C for 16 hours, quenched with IN HCI (0.15 mL) at 0°C, and the solvents were evaporated to give the crude product to be used without further purification. The compounds listed in Table 5, wherein X7 and X9 represent respectively the points of connection to the core structure (C), were prepared by the procedures as exemplified in Example 148A-148F, substituting the conesponding aldehydes for l-methyl-2- formylbenzimidazole, and substituting the conesponding amino acid esters for (L)-methyl t- leucinate hydrochloride. Table 5
Figure imgf000137_0001
Figure imgf000138_0002
Figure imgf000138_0001
Figure imgf000138_0003
Example 159 (2S)-2-[3-({2-[(dimethylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]-3- methylbutanoic acid Example 159A tert-butyl (2S)-2-[3-({2-[(dimethylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l- imidazolidinyl]-3-methylbutanoate Example 273D (0.2 g, 0.54 mmol) was dissolved in toluene: ethanol (2.2 mL, 1:1) and treated with dimethylamine (0.54 mL, 2M in tetrahydrofuran, 2 equivalents) at 70 °C for 3 h. The mixture was cooled to 25 °C and treated with sodium borohydride (20 mg, 3 equivalents) at 25 °C for 68 h. The solvents were evaporated, and the crade residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and the solvents were evaporated. The crade residue was purified using ethyl acetate-ethyl acetate/10% methanol to give 0.11 g (53%o) of the title compound.
Example 159B (2S)-2-[3-({2-[(dimethylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]-3- methylbutanoic acid Example 159A was dissolved in dichloromethane: trifluoroacetic acid (2.4 mL, 1 : 1) at
25 °C for 1 h. The solvents were evaporated to give the title compound used directly for the next step.
Example 160 (2S)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-2,3-dihydro-lH-imidazol-l- yl}butanoic acid
Example 160A N-(2,2-diethoxyethyl)-N-[(2-methyl-l,3-thiazol-4-yl)methyl]amine 4-Chloromethyl-2-methylthiazole (0.6 g, 4 mmol) was added to aminoacetaldehyde diethyl acetal (5 mL, 10 equivalents) dissolved in tetrahydrofuran (15 mL) at 25 °C, and the mixture was stined for 16 h. The solvents were evaporated and the excess aldehyde was distilled from the crade mixture. The crade residue was purified using dichloromethane - dichloromethane/ 10% methanol to give 0.76 g (76%) of the title compound.
Example 160B methyl (2S)-3-methyl-2-{3-[(2-methyl-l,3-tlιiazol-4-yl)methyl]-2-oxo-2,3-dihydro-lH- imidazol- 1 -yl}butanoate Example 160A (0.76 g, 3.1 mmol) was dissolved in tetrahydrofuran (12 mL) and treated with (L)-methyl valinate p-nitrophenylcarbamate (0.92 g, 1 equivalent), triethylamine (0.43 mL, 2 equivalents), and DMAP (60 mg, 1.5 equivalents) at 25 °C for 2 days. The solvents were evaporated, and the crade residue was partitioned between ethyl acetate/10%) sodium carbonate, the organic layer was separated, dried over magnesium sulfate, and the solvents were evaporated. The crade material was dissolved in formic acid (30 mL) at 25 °C for 16 h. the solvents wer evaporated and the crade residue was purified using dichloromethane - ethyl actate to give 0.51 g (53%) of the title compound.
Example 160C Example 160B (0.1 g, 0.32 mmol) was dissolved in tefrahydrofuran:water (1.5 mL,
2:1) and treated with lithium hydroxide (40 mg, 3 equivalents) at 25 °C for 30 min. The mixture was combined with IN HCI (1 mL) and partitioned between ethyl acetate and brine. The organic layer was separated and dried over magnesium sulfate, and the solvents were evaporated to give 95 mg (100%) of the the title compound.
Example 161 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3- { [2-(methoxymethyl)- l,3-thiazol-4-yl]methyl}-2-oxoimidazolidin-l-yl)-3-methylbutanamide Method A Example 146 (62 mg ) was combined with HOBT (39 mg, 1.5 equivalents) and EDAC (55 mg, 1.5 equivalents) in N,N-dimethylformamide (3 mL) and stined for 1 h at 25° C. To this mixture was added N-methylmorpholine (NMM) (42 μL, 2 equivalents) and Example 18 (80 mg, 1 equivalent). The mixture was stined for 16 hrs, evaporated under vacuum, and purified using 3% methanol/dichloromethane to give 54 mg (39%) of the title compound. Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.86 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.78 Hz, 3 H), 1.85 (m, 1 H), 2.15 (m, 1 H), 3.00 (m, 10 H), 3.49 (s, 3 H), 3.64 (d, J=10.85 Hz, 1 H), 3.79 (m, 1 H), 4.17 (m, 1 H), 4.41 (d, J=15.26 Hz, 1 H), 4.51 (d, J=15.26 Hz, 1 H), 4.71 (s, 2 H), 6.51 (d, J=8.48 Hz, 1 H), 7.11 (s, 1 H), 7.17 (m, 5 H), 7.70 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.15 (s, 1 H).
Example 162 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-{3-[(l-methyl-lH- benzimidazol-2-yl)methyl] -2-oxoimidazolidin- 1 -yl} butanamide Method B Example 148F (36 mg) was dissolved in N,N-dimethylformamide (1.0 mL) and treated with Example 18 (44 mg, 1 equivalent), HOBT (14.4 mg, 1 equivalent), N- methylmorpholine (57 μL, 5 equivalents), and benzotriazole- 1-y 1-oxy-fris-pyπolidino- phosphonium hexafluorophosphate (PyBOP) (54.6 mg, 1 equivalent) at 25°C for 16 hrs. The solvents were evaporated, and the residue was purified using 9% methanol/dichloromethane to give 48 mg (62%) of the title compound. Η LNMR (300 MHz, CDC13) δ ppm 0.87 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 0.94 (s, 9 H), 1.90 (m, 1 H), 2.75 (m, 2 H), 2.90 (m, 1 H), 3.09 (m, 7 H), 3.30 (dd, J=8.99, 4.92 Hz, 1 H), 3.81 (s, 3 H), 3.85 (m, 1 H), 4.05 (m, 1 H), 4.67 (d, J-15.26 Hz, 1 H), 4.86 (d, J=15.26 Hz, 1 H), 6.20 (d, J=8.48 Hz, 1 H), 7.12 (m, 5 H), 7.32 (m, 3 H), 7.75 (m, 5 H), 8.19 (s, 1 H). The compounds listed in Table 6, wherein X3, X and X9 represent respectively the points of connection to the core structure (D), were prepared by coupling the conesponding acids (Examples 32-160) with the conesponding amines (Examples 1-31) using procedure exemplified by Example 161 (method A) and Example 162 (method
Figure imgf000140_0001
Table 6
Figure imgf000140_0002
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Example 270 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxoimidazolidin-l-yl}butanamide Example 756 (13 mg, 0.019 mmol) was dissolved in ethanol (0.5 mL) and treated with hydroxylamine hydrochloride (3.9 mg, 3 equivalents) for 3 hrs at 25°C. The solvents were evaporated, and the residue was purified using 8% methanol/dichloromethane to give 5 mg (38%>) ofthe title compound.
Example 271 (2,2-diethoxyethylidyne)-λ4-sulfanylamine 1,1-Diethoxyacetamide (10 g, 0.068 mol) was dissolved in tefrahydrofuran (250 mL) and treated with P4S10 (3 g, 0.1 eq) at 25 °C for 16 h. The solvents were evaporated and diluted with ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, and the solvents were evaporated to give 7.13 g (64%) of the crade product used directly for the next step.
Example 272 ethyl 2-(diethoxymethyl)-l,3-thiazole-4-carboxylate Example 271 (7.13 g, 0.044 mol) was dissolved in ethanol (90 mL) and treated with ethyl bromopyravate (5.5 mL, 1 equivalent) and 3A molecular sieves (20 g) and the mixture was heated at 80 °C for 30 min. The mixture was filtered and the solvents were evaporated. The crade residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine and dried over magnesium sulfate. The solvents were evaporated and the crude residue was purified using dichloromethane with increasing amounts of ethyl acetate up to 10% to give 9.5 g (84%) ofthe thiazole. Example 273 (2S)-N- {(1 S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[3-({2- [(methylamino)methyl]- 1 ,3-thiazol-4-yl}methyl)-2-oxoimidazolidin- 1 -yl]butanamide
Example 273A [2-(diethoxymethyl)- 1 ,3 -thiazol-4-yl]methanol Example 273B 2-(diethoxymethyl)-l,3-tlιiazole-4-carbaldehyde Example 272 (7.8 g, 30 mmol) was dissolved in toluene (60 mL) and treated with diisobutyl aluminum hydride (42 mL, 1.4 equivalents, IM in toluene) at -78 °C for 45 min. The mixture was quenched with ethyl acetate (50 mL) and warmed to 25 °C while adding sodium potassium tartrate (10 mL, 10%) for 2 h. the mixture was exfracted with ethyl acetate, the organic layer was washed with brine, dried over magnesium sulfate, and the solvents were evaporated. Two products were purified using ethyl acetate: hexane (1:1) to give 0.8 g (10%) of Example 273 A and the remaining fractions consisted of crude Example 273B.
Example 273 C tert-butyl (2S)-2-(3 - { [2-(diethoxymethyl)- 1 ,3-thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)- 3-methylbutanoate Example 273B (0.144 g, 0.57 mmol) was dissolved in benzene: ethanol (3 mL, 1:1) treated with the valine analog of Example 32C (0.14 g, 1 equivalent) and the mixture was heated to 70 °C for 1 h. The mixture was cooled to 25 °C and treated with sodium borohydride (75 mg, 3 equivalents) for 2 h. The mixture was partitioned between ethyl acetate and water, the organic layer was washed with saturated sodium bicarbonate, dried over magnesium sulfate and the solvents were evaporated. The crade residue was dissolved in dichloroethane (25 mL) and treated with bis-(p-nitrophenylcarbonate) (0.245 g, 1.2 equivalents) and heated to 60 °C for 16 h. The solvents were evaporated and the crade residue was purified using dichloromethane (100%o) to hexane (100%) to hexane: ethyl acetate (1:1) to give 0.115 g (39%> for 4 steps) ofthe title compound.
Example 273D tert-butyl (2S)-2- {3-[(2-formyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo-l -imidazolidinyl} -3- methylbutanoate Example 273C (0.1 g, 0.24 mmol) was dissolved in acetone (10 mL) and treated with IM HCI (1 mL) at 70 °C for 45 min. The solvents were evaporated and the crude residue was partitioned between ethyl acetate and saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and the solvents were evaporated to give 89 mg (99%) ofthe title compound.
Example 273E tert-butyl (2S)-3-methyl-2-[3-({2-[(methylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l- imidazolidinyl]butanoate Example 273D (0.2 g, 0.54 mmol) was dissolved in toluene (1.1 mL) and ethanol (1.1 mL) and treated with methylamine solution in tetrahydrofuran (0.54 mL, 2M, 2 equivalents) and stined at 70 °C for' 3 h. The mixture was cooled to 25 °C and combined with sodium borohydride (20 mg, 3 equivalents) and stined for 18 h. LThe solvents were evaporated, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer separated, washed with brine and dried over sodium sulfate. The solvents were evaporated and the crude residue was purified using chloroform - 95%> chloroform/5%) methanol to give 0.118 g (56%) ofthe title compound. Example 273F tert-butyl (2S)-2-{3-[(2-{[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]methyl}-l,3- thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl} -3 -methylbutanoate Example 273E (0.115 g, 0.3 mmol) was dissolved in dichloromethane (3 mL), cooled to 0 °C, combined with triethylamine (90 μL, 2.2 equivalents) and fluorenylmethyl chloroformate (86 mg, 1.1 equivalents). The mixture was stined at 0 °C for 1 h, then at 25 °C for 18 h. The solvents were evaporated, and the crude residue was purified using ethyl acetate: hexanes (1:1) to give 0.138 g (76%) ofthe title compound.
Example 273G 9H-fluoren-9-ylmethyl {4-[(3-{(lS)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hyαLxOxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- methylpropyl}-2-oxo-l-imidazolidinyl)methyl]-l,3-thiazol-2-yl}methyl(methyl)carbamate Example 273F (10 mg, 0.017 mmol) was dissolved in trifluoroacetic acid: dichloromethane (1:1, 0.3 mL) at 25 °C for 90 min. The solvents were evaporated, and the crade residue was dissolved in dimethylformamide (0.2 mL) and freated with N-methyl morpholine (3.4 mg, 1.5 equivalents), HOBT (3.4 mg, 1.5 equivalents), EDAC (4.8 mg, 1.5 equivalents), and Example 18 (10 mg, 1.5 equivalents). The mixture was stined at 25 °C for 68 h. The solvents were evaporated and the crude residue was purified using C-18 column to give 8 mg (51%>) ofthe title compound.
Example 273H (2S)-N- {(1 S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2-[3-( {2- [(methylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]butanamide Example 273G (8 mg, 0.008 mmol) was dissolved in acetonitrile (0.1 mL) and treated with diethylamine (2 μL, 3 equivalents) at 25 °C for 1 h. The solvents were evaporated and the residue was purified using C-18 to give 6.5 mg (92%) ofthe title compound. Example 274
(2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(pynolidin-2-ylmethyl)amino]propyl} -3-methyl-2- {3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxoimidazolidin-l-yl}butanamide
Example 274A (2R,3S)-3-amino-l-azido-4-phenylbutan-2-ol A solution of (2R,3S)-3-N-tert-butoxycarbonylamino-l,2-epoxy-4-phenylbutane (1.17 g) in ethano water (45 mL, 4:1) was freated with lithium azide (1.09 g, 5 equivalents) and NH4C1 (1.19 g, 5 equivalents), stined at 75°C for 2 hours and concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated. A solution ofthe residue in dichloromethane/trifluoroacetic acid (40 mL, 1:1) was stined at 25°C for 1 hour and concenfrated to give the title compound.
Example 274B (2S)-N-[(lS,2R)-3-azido-l-benzyl-2-hydroxypropyl]-3-methyl-2-{3-[(2-methyl-l,3-thiazol- 4-yl)methyl]-2-oxoimidazolidin-l-yl}butanamide A solution ofthe product of Example 274A (0.825 g) in N,N-dimethylformamide (30 mL) was treated with EDAC (0.744 g, 1.2 equivalents), HOBT (0.65 g, 1.2 equivalents), N- methyl morpholine (0.88 mL, 2 equivalents) and Example 143D (1.19 g, 1 equivalent), stined at 25°C for 1 hour and concentrated. The residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%)) to give 1.3 g (67%) of title compound.
Example 274C (2S)-N-[(lS,2R)-3-amino-l-benzyl-2-hydroxypropyl]-3-methyl-2-{3-[(2-methyl-l,3-thiazol- 4-yl)methyl] -2-oxoimidazolidin- 1 -yl} butanamide A solution ofthe product of Example 274B (1.3 g) in tetrahydrofuran: water (25 mL, 4:1) was treated with triphenylphosphine (1.4 g, 2 equivalents), stined at 70°C for 2 hours and concentrated. The residue was partitioned between IN HCI and dichloromethane. The aqueous layer was separated and made basic using IN NaOH, extracted with dichloromethane and the organic extract was concentrated. The residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 0.76 g (62%) ofthe title compound. Example 274D tert-butyl 2-[({(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxoimidazolidin-l-yl}butanoyl)amino]-4- phenylbutyl} amino)methyl]pynolidine- 1 -carboxylate A solution ofthe product of Example 274C (59 mg) in ethano benzene (1 mL, 1:1) was treated with N-t-butoxylcarbonyl-(L)-prolinal (26 mg, 1 equivalent), stined at 70°C for 1 hour, cooled at 25°C, freated with NaBH4 (14 mg, 3 equivalents) at 25°C and stined for 16 hours. The mixture was quenched with saturated NH4C1 and partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated to give 85 mg ofthe crade title compound.
Example 274E tert-butyl 2-[(({4-[(hydroxyimino)methyl]phenyl}sulfonyl){(2R,3S)-2-hydroxy-3-[((2S)-3- methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxoimidazolidin- 1 -yl} butanoyl)amino] -4- phenylbutyl} amino)methyl]pynolidine- 1 -carboxylate A solution ofthe product of Example 274D (85 mg) in dichloromethane (0.6 mL) was treated with triethylamine (17 μL, 2 equivalents) and 4-formylbenzenesulfonyl chloride (12 mg, 1 equivalent), stined at 25°C for 2 hours and concentrated. A solution ofthe residue in methanol (1 mL) was freated with hydroxylamine hydrochloride, stined at 25°C for 16 hours and concentrated. The residue was purified by HPLC reverse phase chromatography using water (0.1%> trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 16 mg (20% over 3 steps) ofthe title compound. Example 274F (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(pynolidin-2-ylmethy l)amino]propyl} -3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxoimidazolidin- 1 -yl} butanamide A solution ofthe product of Example 274E (12 mg) in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) was stined at 25°C for 1 hour and concentrated. The residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%>) to give 10 mg (95%) ofthe title compound.
Example 275 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxo-2,3-dihydro-lH-imidazol-l-yl}butanamide Example 160C (62 mg, 0.22 mmol) was combined with HOBT (43 mg, 1.5 equivalents) and EDAC (60 mg, 1.5 equivalents) in N,N-dimethylformamide (3 mL) and stined for 1 hour at 25°C. To this mixture was added N-methyl morpholine (43 μL, 3 equivalents) Example 18 (88 mg, 1.1 equivalents). The mixture was stined for 16 hours, evaporated, and chromatographed, eluting with 2.5% methanol/dichloromethane to give 60 mg (41%)) of title compound.
Example 276 (2S)-2-[3-(3-aminobenzyl)-2-oxoimidazolidin-l-yl]-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylbutanamide Example 174 (68 mg, 0.09 mmol) was dissolved in ethyl acetate (1 mL) was freated with 10%) Pd/C (14 mg) for 2 h. After work-up, the crade residue was purified using 3% methanol/chloroform to give 53 mg (82%) ofthe title compound. Example 277 (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(l -oxido-3- pyridinyl)methyl]-2-oxo- 1 -imidazolidinyl}pentanamide Example 179 (14.8 mg) was dissolved in tefrahydrofuran (0.25 mL) and freated with m-chloroperbenzoic acid (6 mg, 1.5 equivalents) at 25°C for 3 h. The solvents were evaporated, and the residue was purified using 7%> methanol/dichloromethane to give 12.5 mg (83%>) ofthe title compound.
Example 278 (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(l- oxidopyridin-4-yl)methyl]-2-oxoimidazolidin- 1 -yl}pentanamide Example 181 (10.4 mg) was dissolved in tefrahydrofuran (0.25 mL) and treated with m-chloroperbenzoic acid (6 mg, 1.5 equivalents) at 25°C for 3 h. The solvents were evaporated, and the residue was purified using 7%> methanol/dichloromethane to give 10.5 mg (98%) ofthe title compound.
Example 279 (2S,3S)-2-(3-{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}-2-oxoimidazolidin-l-yl)-N- {(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide Example 279A tert-butyl (2S,3S)-2-(3-{[2-(diethoxymethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l- imidazolidinyl)-3-methylpentanoate Example 273B (0.86 g, 4 mmol) was dissolved in ethanol: benzene (12 mL, 1:1) and treated with Example 32C (0.55 g, 2.4 mmol) at 70 °C for 1 h. The mixture is cooled to 25 °C and freated with sodium borohydride (0.275 g, 3 equivalents) for 2 h. The mixture is quenched with methanol and the solvents were evaporated. The crude residue was dissolved in dichloroethane (100 mL) and freated with bis-p-nitrophenyl carbonate (0.9 g, 1.2eq) at 70 °C for 16 h. The solvents were evaporated, and the crude residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate and the solvents were evaporated. The crade residue was purified using dichloromethane: hexanes (1:1) - hexanes - hexanes/ethyl acetate (1 : 1) to give 0.72 g (66%) ofthe title compound. Example 279B tert-butyl (2S,3S)-2-{3-[(2-formyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3- methylpentanoate Example 279A (0.72 g, 1.6 mmol) was dissolved in acetone (35 mL) and freated with IN HCI (3.5 mL) at 70 °C for 45 min. The solvents were evaporated, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated and washed with brine, dried over magnesium sulfate, and the solvents were evaporated to give 0.584 g (97% crude) ofthe title compoimd.
Example 279C tert-butyl (2S,3S)-2-(3-{[2-(hydroxymethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l- imidazolidinyl)-3-methylpentanoate Example 279B(0.2 g, 0.54 mmol) was dissolved in ethanol (5 mL) and treated with sodium borohydride (30 mg, 1.5 equivalents) and stined for 2 h. The solvents were evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer separated, washed with brine and dried over magnesium sulfate. The solvents were evaporated and the crade residue was used directly for the next reaction.
Example 279D tert-butyl (2S,3S)-3-methyl-2-{3-[(2-{[(methylsulfonyl)oxy]methyl}-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}pentanoate Example 279C (0.2 g, 0.3 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 °C, combined with triethylamine (0.22 mL, 3 equivalents) and methanesulfonyl chloride (0.06 mL, 1.5 equivalents). The mixture was stined at 0 °C for 90 min. The solvents were evaporated, and the crade residue was diluted with ethyl acetate and washed withl0%> citric acid, saturated sodium bicarbonate, brine, and dried over magnesium sulfate to give 0.25 g of crade Example 279D residue which was used directly for the next reaction.
Example 279E tert-butyl (2S,3S)-2-(3-{[2-(azidomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)- 3-methylpentanoate Example 279D (0.25 g) was dissolved in dimethylformamide (4 mL) freated with lithium azide (0.255 g, 10 equivalents) and stined at 50 °C for 1 h. The solvents were evaporated and the residue was diluted with ethylacetate and washed with water, brine, and dried over magnesium sulfate. The solvents were evaporated to give 0.192 g crude azide.
Example 279F (2S,3S)-2-(3-{[2-({[(9H-fluoren-9-ylmethoxy)carbonyl]amino}methyl)-l,3-thiazol-4- yl]methyl} -2-oxo- 1 -imidazolidinyl)-3-methylpentanoic acid Example 279E (0.19 g, 0.47 mmol) was dissolved in tefrahydrofuran (4 mL) and water (1 mL) and treated with triphenylphosphine (0.247 g, 2 equivalents) and stined at 50 °C for 1 h. The solvents were evaporated and the crade residue (0.127 g) was dissolved in acetonitrile (2.5 mL) and water (0.7 mL) and treated with sodium bicarbonate (67 mg, 2.4 equivalents) and fluorenylmethyl chloroformate (103 mg, 1.2 equivalents) and stined at 25 °C for 90 min. The solvents were evaporated and the crade residue was diluted with ethyl acetate and washed with water, brine, dried over magnesium sulfate, and filtered. The solvents were evaporated and the crude residue was purified using chloroform: ethyl acetate 4:1 - 1:1 to give 0.2 g (70%) ofthe ester. This ester was dissolved in dichloromethane: trifluoroacetic acid (5 mL, 3:2) and stined at 25 °C for 2 h. The solvents were evaporated to give 0.12 g ofthe title compound.
Example 279G (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-{3-[(2-{[(9H-fluoren-9- ylmethyl)amino]methyl} - 1 ,3-thiazol-4-yl)methyl] -2-oxoimidazolidin- 1 -yl} -3- methylpentanamide Example 279F (15 mg, 0.027 mmol) was dissolved in N,N-dimethylformamide (0.3 mL) and treated with EDAC (8 mg, 1.5 equivalents), HOBT (6 mg, 1.5 equivalents), N- methyl morpholine (7 μL, 2.5 equivalents), followed by Example 18 (17 mg, 1.5 equivalents) at 25°C for 16 hrs. The solvents were evaporated, and the residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (75:25) to acetonitrile (100%) to give 12.3 mg (46%) ofthe title compound.
Example 279H (2S,3 S)-2-(3 - { [2-(aminomethyl)- 1 ,3-thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)-N- {(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide Example 279G (12 mg) was dissolved in acetonitrile (0.2 mL) and treated with diethylamine (3 μL, 3 equivalents) at 25°C for 2 h. The solvents were evaporated, and the residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (75:25) to acetonitrile (100%) to give 9.8 mg (92%>) ofthe title compound.
Example 280 (2S,3S)-2-(3-{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N- {(1 S,2R)-1 -benzyl-3-[(cyclobutylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methylpentanamide
Example 280A 9H-fluoren-9-ylmethyl {4-[(3-{(lS,2S)-l-[({(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}amino)carbonyl]-2- methylbutyl}-2-oxo-l-imidazolidinyl)methyl]-l,3-thiazol-2-yl}methylcarbamate In a similar manner to Example 279G, Example 280A was prepared using Example 279F (15 mg, 0.027mmol), N-methyl morpholine (7 μL, 2.5 equivalents), HOBT (6 mg, 1.5 equivalents), EDAC (8 mg, 1.5 equivalents) and Example 19 (18 mg, 1.5 equivalents) in dimethylfomamide (0.3 mL) to give 11.8 mg (46%>) after purification on C-18 using 75%> water/0. l%trifluoroacetic acid /25%o acetonitrile - 100% acetonitrile.
Example 280B 9H-fluoren-9-ylmethyl {4-[(3-{(lS,2S)-l-[({(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}amino)carbonyl]-2- methylbutyl}-2-oxo-l-imidazolidinyl)methyl]-l,3-thiazol-2-yl}methylcarbamate In a similar manner to Example 279H, Example 280A (11 mg, 0.013 mmol) was treated with diethylamine (3 μL). The crade product was purified by C-18 using 95%> water/0. l%)trifluoroacetic acid /5% acetonitrile - 100%> acetonitrile to give 7.8 mg (76%) of the title compound. Example 281 (2S,3S)-2-(3-{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N- {(lS,2R)-l-benzyl-3-[(cyclopentyhnethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methylρentanamide In a similar manner to Example 280, Example 281 was prepared using Example 279F
(75 mg, 0.14mmol), N-methyl morpholine (38 μL, 2.5 equivalents), HOBT (28 mg, 1.5 equivalents), EDAC (39 mg, 1.5 equivalents) and Example 27 (91 mg, 1.5 equivalents) in dimethylfomamide (1.2 mL) to give 79.5 mg (60%) after purification on C-18 using 75%> water/0. l%trifiuoroacetic acid /25%> acetonitrile - 100% acetonitrile. This product was treated with diethylamine (20 μL, 3 equivalents) as in Example 279H. The crude product was purified by C-18 using 95% water/0. l%trifluoroacetic acid /5% acetonitrile - 100% acetonitrile to give 49 mg (70%) ofthe title compound.
Example 282 (2S,3S)-N- {(1 S,2R)-1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({2-[N- hydroxyethanimidoyl]pyridin-4-yl}methyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl]-3- methylpentanamide Example 405 (30 mg, 0.039 mmol) was dissolved in ethanol (1 mL) and freated with NaBH4 (7 mg, 5 equivalents) at 25°C for 16 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, dried over NaSO4, filtered and the solvents were evaporated. The residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) at 25°C for 1 h and the mixture was partitioned between water and ethyl acetate, the organic layer was washed with saturated NaHCO3, water, brine, and dried over NaSO4, filtered and the solvents were evaporated. The residue was purified using 7% methanol/dichloromethane to give 25.5 mg (88%o) ofthe title compound.
Example 283 (2R,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-[3-({2- [(isopropylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]-3- methylpentanamide
Example 283A tert-butyl (2S,3S)-2-[3-({2-[(isopropylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l- imidazolidinyl]-3-methylpentanoate A solution of Example 273D (65 mg) in toluene: ethanol (0.7 mL, 1:1) was treated with isopropylamine (0.14 mL, 10 equivalents), stined at 70°C in a capped vial for 2 hrs. The mixture was cooled to 25°C and NaBH4 (19 mg, 3 equivalents) was added and the mixture was stined at 25°C for 3 days. The solvents were evaporated, and the residue was partitioned between ethyl acetate and saturated NaHCO3, the organic layer was separated and washed with brine, dried over MgSO4, filtered and evaporated to give 59 mg ofthe title compound.
Example 283B (2S,3S)-2-{3-[(2-{[[(9H-fluoren-9-ylmethoxy)carbonyl](isopropyl)amino]methyl}-l,3- , thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylpentanoic acid A solution ofthe product of Example 283A (59 mg) in acetonitrile (0.9 mL) and water (0.3 mL) was treated with NaHCO3 (34 mg, 2.4 equivalents) followed by 9-fluorenylmethyl chloroformate (53 mg, 1.2 equivalents) at 25°C for 1.5 h. The solvents were evaporated and the residue was purified using ethyl acetate: chloroform (1:4) to give 47 mg (40%) of FMOC- amine which was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) and stined at 25 °C for 1 h. The solvents were evaporated, and the acid was used directly for the next step.
Example 283C 9H-fluoren-9-ylmethyl {4-[(3- {(1 S,2S)-l-[( {(1 S,2R)- 1 -benzyl-3-[(cyclopentylmethyl)( {4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2 -hydroxypropyl} amino)carbonyl]-2- methylbutyl}-2-oxo-l-imidazolidinyl)methyl]-l,3-thiazol-2-yl}methyl(isopropyl)carbamate A solution of crude Example 283B dissolved in N,N-dimethylformamide (0.6 mL) was treated with EDAC (16 mg, 1.2 equivalents), HOBT (11 mg, 1.2 equivalents) and N- methylmoφholine (18 μL, 2.4 equivalents) followed by the Example 27 (36 mg, 1.2 equivalents) at 25°C for 16 hrs. The solvents were evaporated, and the residue was purified using HPLC reverse phase chromatography using water (0.1 %> trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 38.5 mg (55%) ofthe title compound. Example 283D (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-[3-({2- [(isopropylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]-3- methylpentanamide
Example 284 (2R,3R)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-[3-({2- [(isopropylamino)methyl] - 1 ,3 -thiazol-4-yl} methyl)-2-oxo- 1 -imidazolidinyl] -3 - methylpentanamide A solution of Example 283C (38.5 mg, 0.038 mmol) in acetonitrile (0.5 mL) and diethylamine (9 μL, 3 equivalents) was stined at 25°C for 1 h. The solvents were evaporated and the residue was purified by HPLC reverse phase chromatography using water (0.1 %> trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%>) to give 30.9 mg of amines. The two products were separated by preparative TLC using 0.5 mm silica gel plates, eluting with 5% methanol/chloroform/0.2%) ammomum hydroxide to give 7.3 mg of Example 283D and 7.4 mg of Example 284.
Example 285 (2S,3S)-2-(3-{3-[amino(hydroxyimino)methyl]benzyl}-2-oxo-l-imidazolidinyl)-N-{(lS,2R)- l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide Example 201 (65 mg) was dissolved in ethanol (1 mL) and freated with triethylamine (0.13 mL, 10 equivalents) and hydroxylamine hydrochloride (25 mg, 4 equivalents) at 50°C for 6 h. The mixture was partitioned between water and ethyl acetate, the organic layer was separated, dried over Na2SO4, filtered and the solvents were evaporated. The residue was purified using 3% methanol/chloroform to give 57 mg (84%>) ofthe title compound.
Example 286 (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-{3-[3- (hydroxymethyl)benzyl]-2-oxo-l-imidazolidinyl}-3-methylpentanamide
Example 286A 6-[(trityloxy)methyl]pyridine-2-carbaldehyde 2,6-Dimethanol pyridine (1 g) was prepared per J. Org. Chem. 63, 3884-3894 (1998) to give 330 mg (12%>) ofthe mono-trityl analog. The trityl ether (0.33 g) was dissolved in dichloromethane (2 mL) and stined at 25°C with manganese dioxide (0.5 g, 7 equivalents) for 3 days. The mixture was filtered through Celite©, and purified using dichloromethane to give 0.284 g (86%) ofthe title compound.
Example 286B tert-butyl (2S,3S)-3-methyl-2-[2-oxo-3-({6-[(frityloxy)methyl]pyridin-2- yl}methyl)imidazolidin-l-yl]pentanoate A solution ofthe product of Example 286A (0.28 g) in dichloromethane (5 mL) was treated with Example 32C (0.17 g, 1 equivalent) and MgSO (1 g) and the mixture was stined at 25°C for 2 h. The mixture was filtered and the solvents were evaporated. The residue was dissolved in methanol (5 mL) and treated withNaBH (42 mg, 1.5 equivalents) at 25°C for 1 h. The mixture was partitioned between water and ethyl acetate, the organic layer was separated and dreid over Na2SO4, filtered and the solvents were evaporated. The residue was used directly for the next step. The crude diamine was dissolved in N,N-dimethylformamide (15 mL) and treated with bis-(p-nifrophenylcarbonate (0.27 g, 1.2 equivalents) at 50°C for 3 h. The mixture was partitioned between water and ethyl acetate and the organic layer was separated, washed with saturated NaHCO3, dried over NaSO , filtered and the solvents were evaporated. The residue was purified using 5% ethyl acetate in dichloromethane to give 0.35 g (76%) ofthe title compound.
Example 286C (2S ,3 S)-3 -methyl-2- [2-oxo-3 -( { 6- [(trityloxy)methyl]pyridin-2-yl} methyl)imidazolidin- 1 - yfjpentanoic acid A solution ofthe product of Example 286B (0.35 g) in trifluoroacetic acid: dichloromethane (3 mL, 2:1) was stined at 25°C for 2 hrs. The solvents were evaporated and the residue was directly used for the next step.
Example 286D (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3 -methyl-2- [2-oxo-3-( {6- [(trityloxy)methyl]pyridin-2-yl}methyl)imidazolidin-l-yl]pentanamide A solution ofthe product of Example 286C (0.35 g, 0.59 mmol) in N,N- dimethylformamide (4 mL) was combined with EDAC (0.17 g, 1.5 equivalents), HOBT (0.12 g, 1.5 equivalents), N-methylmorpholine (0.13 mL, 2 equivalents) followed by the Example 18 (0.27 g, 1.1 equivalents). The mixture was stined at 25°C for 16 hrs and partitioned between saturated NaHCO3 and ethyl acetate. The organic layer was separated and dried over Na2SO4) filtered and the solvents were evaporated. The residue was purified first using 2% methanol/chloroform followed by ethyl acetate: hexanes (1 :2) to give 0.243 g (43%) of the title compound.
Example 286E (2S,3S)-N- {(1 S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3 - { [6- (hydroxymethyl)pyridin-2-yl]methyl} -2-oxoimidazolidin- 1 -yl)-3-methylpentanamide A solution ofthe product of Example 286D (0.166 g) in methanol: dichloromethane (2 mL, 3:2) at 0°C was treated with concenfrated HCI (1 mL). The mixture was stined at 25°C for 30 min and partitioned into sat NaHCO3 and dichloromethane. The organic layer was separated and dried over NaSO4, filtered, and the solvents were evaporated. The residue was purified using 4% methanol/chloroform to give 69 mg (56%>) ofthe title compound. Example 287 (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({6- [(hydroxyimino)methyl]-2-pyridinyl}methyl)-2-oxo-l-imidazolidinyl]-2,3- dimethylpentanamide Example 286E (10 mg, 0.014 mmol) was dissolved in dichloromethane (50 mL) and treated with MnO2 (72 mg, 50 equivalents) at 25°C for 16 hrs. Continue to add enough MnO2 to complete the reaction. The mixture was filtered through Celite®, and the solvents were evaporated. The crade aldehyde was dissolved in methanol (1 mL) and freated with hydroxylamine hydrochloride (10 mg, 1.1 equivalents) at 25°C for 1.5 h. The mixture was partitioned between sat NaHCO3 and ethyl acetate, the organic layer was separated, dried over Na2SO4, filtered and the solvents were evaporated. The residue was purified using ethyl acetate: hexanes (2:1) to give 1.7 mg (17%) ofthe title compound.
Example 288 (2S)-N- {(1 S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E
(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3- {[6-(l-hydroxyethyl)- 2-pyridinyl]methyl}-2-oxo-l-imidazolidinyl)-3,3-dimethylbutanamide
Example 288A (2S)-2-{3-[(6-acetyl-2-ρyridinyl)methyl]-2-oxo-l-imidazolidinyl}-N-{(lS,2R)-l-benzyl-2- hydroxy-3-[({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3- dimethylbutanamide Example 122 (0.17 g) was dissolved in N,N-dimethylformamide (2 mL) and treated with EDAC (0.19 g, 2.7 equivalents), HOBT (0.134 g, 2.7 equivalents), N-methylmorpholine (88 μL, 2.1 equivalents) and Example 18 (0.28 g, 1.78 equivalents) at 25°C for 2.5 days. The mixture was partitioned between IN NaHCO3 and ethyl acetate. The organic layer was separated, dried over Na2SO4, filtered and the solvents were evaporated. The residue was purified using ethyl acetate: hexanes (3:2) followed by using 3% methanol/dichloromethane to give 99 mg (35%>) ofthe title compound.
Example 288B , (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3 - { [6-(l - hydroxyethyl)pyridin-2-yl]methyl}-2-oxoimidazolidin-l-yl)-3,3-dimethylbutanamide A solution ofthe product of Example 288A (86 mg) in methanol (1.5 mL) was treated with NaBH (8.8 mg, 2 equivalents) at 0°C. The mixture was stined for 1 h at 25°C and quenched by adding acetone (0.2 mL). The solvents were evaporated, and the residue was purified using 7% methanol/dichloromethane to give 83 mg (96%») ofthe title compound.
Example 289 (2S,3S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-l-imidazolidinyl}pentanoic acid
Example 289A tert-butyl (2S,3S)-2-[(2-ethoxy-2-oxoethyl)amino]-3-methylpentanoate To a solution of (L)-iso-leucine tert-butyl ester hydrochloride (5 g, 22.34 mmol) in N,N-dimethylformamide (30 mL) was added triethylamine (3.1 mL, 22.34 mmol), and the mixture was stined for 1 h. The reaction was filtered to remove solid salts, and the filtrate was treated with triethylamine (9.3 mL, 67.0 mmol) and ethyl bromoacetate (9.9 mL, 67.0 mmol), and the reaction was stined for 3 h at 25 °C. The reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give 5.7 g (93%) ofthe product which was used without further purification.
Example 289B tert-butyl (2S,3S)-2-[(aminocarbonyl)(2-ethoxy-2-oxoethyl)amino]-3-methylpentanoate To Example 289A (5.7 g, 20.9 mmol) in dichloromethane (60 mL) at 0 °C was added chlorosulfonyl isocyanate (2.7 mL, 31.0 mmol) and the mixture was stined at 0 °C for 16 h. Water (60 mL) was added to the cold reaction and the mixture was warmed to room temperature and stined for 4 h. The reaction was partitioned between dichloromethane and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give 6.83 g ofthe product which was used without further purification.
Example 289C tert-butyl (2S,3S)-2-(2,4-dioxo-l-imidazolidinyl)-3-methylpentanoate To Example 289B (6.8 g, 20.9 mmol) in methanol (30 mL) was added triethylamine (5.6 mL, 40.2 mmol), and the mixture was stined at 50 °C for 2 h. The solvent was evaporated and the residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with 30%> ethyl acetate in dichloromethane to give 2.53 g (47%) ofthe title compound
Example 289D tert-butyl (2S,3S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-l- imidazolidinyl}pentanoate To Example 289C (0.107 g, 0.396 mmol) in dichloromethane (2 mL) at 0 °C were added 6-methyl-2-pyridinemethanol (0.053 mg, 0.435 mmol), triphenylphosphine (0.135 g, 0.515 mmol), followed by diethyl azodicarboxylate (0.080 mL, 0.515 mmol), and the mixture was stined at room temperature for 16 h. Water (2 mL) was added and the reaction was stined for 2 h at room temperature. The reaction was partitioned between dichloromethane and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated. The residue was purified using a gradient starting with dichloromethane and ending with 30% ethyl acetate in dichloromethane to give 0.154 g (94% yield) ofthe title compound.
Example 289E (2S,3S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-l-imidazolidinyl}pentanoic acid To Example 289D (0.154 g, 0.410 mmol) in dichloromethane (3 mL) was added trifluoracetic acid (3 mL), and the mixture was stined at room temperature for 16 h. The solvent was evaporated and the product was purified by reversed phase (CI 8) chromatography eluting with a gradient starting with 5% acetonitrile in water (0.1 %> trifluoroacetic acid) and ending with acetonitrile to give 0.153 g (93%) as the trifluoroacetic acid salt.
Example 290 (2S)-2- {3-[(2-ethyl-l ,3-thiazol-4-yl)methyl]-2,4-dioxo- 1 -imidazolidinyl} -3-methylbutanoic acid Example 290A tert-butyl (2S)-2-[(2-ethoxy-2-oxoethyl)amino]-3-methylbutanoate To a solution of (L)-valine tert-butyl ester hydrochloride (4.94 g, 23.6 mmol) in N,N- dimethylformamide (55 mL) was added triethylamine (3.28 mL, 1 equivalent), and the mixture was stined for 1 h. The reaction was filtered to remove solid salts, and the filtrate was freated with triethylamine (9.85 mL, 3 equivalents) and ethyl bromoacetate (7.84 mL, 3 equivalents), and the reaction was stined for 3 h at 25 °C. The reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give 4.48 g (78%>) ofthe product which was used without further purification. Example 290B tert-butyl (2S)-2-[(aminocarbonyl)(2-ethoxy-2-oxoethyl)amino]-3-methylbutanoate Example 290A (4.48 g, 18.3 mmol) was dissolved in dichloromethane (30 mL) at 0 °C and was treated with chlorosulfonyl isocyanate (2.07 mL, 1.3 equivalents) and the mixture was stined at 0 °C for 16 h. Water (60 mL) was added to the cold reaction and the mixture was warmed to 25 °C and stined for 4 h. The reaction was partitioned between dichloromethane and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give crade product which was used without further purification.
Example 290C tert-butyl (2S)-2-(2,4-dioxo-l-imidazolidinyl)-3-methylbutanoate Example 290B (crade product) was dissolved in methanol (30 mL) and was treated with triethylamine (5.07 mL, 2 equivalents), and the mixture was stined at 50 °C for 2 h. The solvent was evaporated and the residue was purified using dichloromethane (100%>) - 25%> ethyl acetate/dichloromethane to give 2.97 g (63%>) ofthe title compound.
Example 290D tert-butyl (2S)-2-{3-[(2-ethyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl}-3- methylbutanoate Example 290C (0.076 g, 0.297 mmol) was dissolved in N,N-dimethylfoπnamide (1.5 mL) at 0 °C and treated with sodium hexamethyldisilazide (0.33 mL, 1.1 equivalents, IM in tetrahydrofuran) and the mixture is stined for 1 h. The 4-chloromethyl-2-ethylthiazole (0.048 mg, 1 equivalent) was added (dissolved in 0.5 mL N,N-dimethylformamide) and the mixture was warmed to 25 °C for 2 h, heated to 75 °C for 18 h. The mixture was quenched with saturated ammonium chloride and partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated. The residue was purified using hexanes (100%) - 65%> hexanes/ethyl acetate to give 77 mg (68%> yield) of the title compound. Example 290E (2S)-2-{3-[(2-ethyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl}-3-methylbutanoic acid Example 290E (75 mg, 0.196 mmol) was dissolved in dichloromethane (1 mL) and trifluoracetic acid (1 mL), and the mixture was stined at room temperature for 1 h. The solvent was evaporated and the crade product was used directly for coupling procedures. The compounds listed in Table 7, wherein Xπ and X7 represents the points of connection to the core structure (E), were prepared by the procedures as exemplified in
Examples 289A-289E and
Figure imgf000169_0001
Table 7
Figure imgf000169_0002
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Example 361 (2S)-2-[3-({2-[(dimethylamino)methyl]-l,3-thiazol-4-yl}methyl)-2,4-dioxo-l- imidazolidinyl] -3 -methylbutanoic acid
Example 361 A tert-butyl (2S)-2-(3-{[2-(diethoxymethyl)-l,3-thiazol-4-yl]methyl}-2,4-dioxo-l- imidazolidinyl)-3-methylbutanoate Example 290C (25 mg, 0.098 mmol) was dissolved in dichloromethane (1 mL) and treated with Example 273 A (21.2 mg, 1 equivalent), triphenylphosphine (31 mg, 1.2 equivalents), and diethyldiazodicarboxylate (18.2 μL, 1.2 equivalents), the mixture was stined at 25 °C for 1 h, quenche with water, the organic layer was separated, dried over magnesium sulfate, filtered, and the solvents were evaporated. The crade residue was purified using dichloromethane (100%) - 20% ethyl acetate/dichloromethane to give 28 mg (63%) ofthe title compound.
Example 36 IB tert-butyl (2S)-2-{3-[(2-formyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl}-3- methylbutanoate Example 361 A (0.31 g, 0.68 mmol) was dissolved in acetone (14 mL) and IM HCI (1.4 mL) and heated to 70 °C for 1 h. The solvents were evaporated, and the residue was partitioned between ethyl acetate and brine, the organic layer was separated, washed with water, dried over magnesium sulfate, and the solvents were evaporated to give crade 0.189 g (73%>) ofthe title compound. Example 36 IC tert-butyl (2S)-2-[3-({2-[(dimethylamino)methyl]-l,3-thiazol-4-yl}methyl)-2,4-dioxo-l- imidazolidinyl]-3-methylbutanoate Example 361B (0.12 g, 0.31 mmol) was dissolved in ethanol: benzene (1.2 mL, 1:1) and treated with dimethylamine (0.79 mL, 2M in tefrahydrofuran) and heated to 70 °C for 2 h. The mixture was cooled to 25 °C and treated with sodium cyanoborohydride (39.5 mg, 2 equivalents) and acetic acid (90 μL, 5 equivalents) and the reaction was quenched by saturated ammonium chloride after 1 h. The mixture was partitioned between water and ethyl acetate, the organic layer was separated, washed with brine, dried over magnesium sulfate and the solvents were eveaporated. The crade residue was purified using dichloromethane (100%) - 4% methanol/dichloromethane to give 63 mg (49%) ofthe title compound. Example 361D (2S)-2-[3-( {2-[(dimethylamino)methyl]- 1 ,3-thiazol-4-yl}methyl)-2,4-dioxo- 1 - imidazolidinyl] -3 -methylbutanoic acid Example 361C (52 mg, 0.127 mmol) was dissolved in trifluoroacetic acid dichloromethane (2 mL, 1:1) at 25 °C for 1 h. The solvents were evaporated to give the crude acid trifluoroacetic acid salt.
Example 362 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-(3-{[2-(methoxymethyl)- l,3-thiazol-4-yl]methyl}-2,4-dioxo-l-imidazolidinyl)-3-methylbutanamide Example 294 (47 mg) is combined with HOBT (28 mg, 1.5 equivalent) and EDAC (32 mg, 1.5 equivalents) in N,N-dimethylformamide (1 mL) and stined for 1 h at 25° C. To this mixture is added N-methylmorpholine (NMM) (30 μL, 2 equivalents) and Example 18 (57 mg, 1 equivalent). The mixture is stined for 16 h, evaporated under vacuum, and purified by HPLC (reverse phase; 95%> water(0.1% trifluoroacetic acid)/ 5%> acetonitrile to 100% acetonitrile; flow =10 mL/minute; time = 30 minute) to give 51 mg (50%) ofthe title compound. 1H NMR (300 MHz, CDC13) δ ppm 0.79 (t, J=7.12 Hz, 6 H), 0.86 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.08 (m, 1 H), 2.66 (dd, J=13.90, 10.85 Hz, 1 H), 2.84 (m, 1 H), 3.12 (m, 5 H), 3.47 (s, 3 H), 3.60 (d, J=17.97 Hz, 1 H), 3.85 (m, 2 H), 4.23 (m, J=4.41 Hz, 1 H), 4.70 (s, 2 H), 4.73 (d, J=14.58 Hz, 1 H), 4.81 (d, J=15.26 Hz, 1 H), 6.39 (d, J=8.82 Hz, 1 H), 7.07 (m, 5 H), 7.24 (s, 1 H), 7.72 (d, J=8.14 Hz, 2 H), 7.80 (d, J=8.48 Hz, 2 H), 8.17 (s, I H). The compounds listed in Table 8, wherein X7, Xl ls and X3 represent respectively the points of connection to the core structure (F), were prepared by coupling the conesponding acids (Example 291-360) with the conesponding amines (Example 1-31), using the procedure as exemplified by Example 362 (Method A) or Example 162 (Method B).
Figure imgf000175_0001
Table 8
Figure imgf000175_0002
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Example 401 (2S)-2-[3-(3-aminobenzyl)-2,4-dioxo-l-imidazolidinyl]-N-{(lS,2R)-l-benzyl-2-hydroxy-3- [({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3- methylbutanamide Example 363 (75 mg) was dissolved in ethyl acetate (1 mL) and combined with 10%> Pd/C (30 mg), a hydrogen balloon, and stined at 25 °C for 2 h. The mixture was filtered, and the solvents were evaporated. The residue was purified using 2% methanol/CHCl3 to give 45 mg (63%) ofthe title compound.
Example 402 (2S)-N- {(1 S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-(3-{3-[N- hydroxyethanimidoyl]benzyl}-2,4-dioxo-l-imidazolidinyl)-3-methylbutanamide Example 376 (90 mg, 0.12 mmol) was dissolved in ethanol (2 mL) and freated with hydroxylamine hydrochloride (34 mg, 4 equivalents) and triethylamine (0.17 mL, 10 equivalents) at 50 °C for 3 h. The mixture was cooled to 25 °C and partitioned between water and ethyl acetate. The organic layer was dried with sodium sulfate and the solvents were evaporated. The crude residue was purified using 1% methanol/chloroform to give 55 mg (60%) ofthe title compound.
Example 403 (2S)-2- {3-[3-(aminomethyl)benzyl]-2,4-dioxo-l -imidazolidinyl} -N- {(1 S,2R)-1 -benzyl-2- hydroxy-3-[({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3- methylbutanamide Example 382 (10 mg, 0.013 mmol) was dissolved in ethyl acetate (0.5 mL) and combined with Lindlar's catalyst (6 mg) and a hydrogen balloon and stined for 2 h. The mixture was filtered, and the solvents were evaporated. The residue was purified on florasil using 10% methanol/dichloromethane to give 5 mg (50%) ofthe title compound.
Example 404
(2S,3S)-2-[3-(3-aminobenzyl)-2,4-dioxo-l-imidazolidinyl]-N-{(lS,2R)-l-benzyl-2-hydroxy- 3-[({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3- methylpentanamide Example 390 (66 mg, 0.088 mmol) was dissolved in ethyl acetate (1 mL) and treated with 10%) Pd/C (20 mg) and stined at 25 °C under a hydrogen balloon for 3.5 h. The catalyst was filtered, and the solvents were evaporated. The crude residue was purified using 2%> methanol/chloroform to give 51 mg (80%o) ofthe title compound. Example 405 (2S,3S)-N- {(1 S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({2-[N- hydroxyethanimidoyl]-4-pyridinyl}methyl)-2,4-dioxo-l-imidazolidinyl]-3- methylpentanamide Example 381 (20 mg, 0.026 mmol) was dissolved in ethanol (0.3 mL) and treated with hydroxylamine hydrochloride (7 mg, 4 equivalents) and triethylamine (37 μL, 10 equivalents) at 50 °C for 6 h. The mixture was cooled to 25 °C and partitioned between water and ethyl acetate. The organic layer was dried with sodium sulfate and the solvents were evaporated. The crade residue was purified using 5% methanol/chloroform to give 19 mg (100%) of the title compound.
Example 406 methyl (2S,3S)-3-methyl-2-{[(4-nifrophenoxy)carbonyl]amino}pentanoate To a solution of (L)-methyl wo-leucinate hydrochloride (2.5 g, 13.75 mmol) in dichloromethane (35 mL) at 0 °C were added 4-nifrophenyl chloroformate (3.05, 15.13 mmol) and N-methylmorpholine (3.2 mL, 29.11 mmol), and the mixture was stined at room temperature for 64 hours. The reaction was partitioned between dichloromethane and saturated NaHCO3, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give the product (4.19 g, 98%> yield), which was used without further purification.
Example 407 methyl (2S)-3-methyl-2- {[(4-nifrophenoxy)carbonyl]amino}butanoate ( )-Methyl valinate (1 g) was dissolved in dichloromethane (10 mL) and freated with bis-(4-nitrophenyl) carbonate (1.2 g, 1.1 equivalents) and N-methylmorpholine(1.5 mL, 2.5 equivalents) at 0 °C for 4 h. The reaction was quenched with IM NaHCO3, and the organic layer was separated, washed with brine, dried with Na2SO4, filtered, and evaporated. The residue is purified using ethyl acetate/hexanes (2:3) to give 1.65 g (96%) ofthe title compound.
Example 408 (2S)-3-methyl-2-[({methyl[(2-methyl-l,3-thiazol-4- yl)methyl] amino} carbonyl)amino]butanoic acid
Example 408A N-methyl(2-methyl-l,3-thiazol-4-yl)methanamine 2-Methyl-4-(chloromethyl)thiazole (2.94 g, CAS#39238-07-8) was dissolved in 40% methylamine (39 mL, 25 equivalents) at 25 °C for 1 h. The mixture was evaporated and purified using 10%> methanol/dichloromethane with 0.5% ΝH4OH to give 2.83 g (99%) ofthe amine. Example 408B methyl (2S)-3-methyl-2-[({methyl[(2-methyl-l ,3-thiazol-4- yl)methyl] amino } carbonyl)amino]butanoate Example 408A (2.83 g) was dissolved in tefrahydrofuran (80 mL) and freated with triethyl amine (2.8 mL, 1 equivalent), DMAP (0.28 g, 0.02 equivalent), and Example 407 (5.9 g, 1 equivalent) at 25 °C for 16 h. The mixture was quenched with 10%> K2CO3, and the organic layer was separated, dried with Na2SO4, filtered, and evaporated to give the crude thiazole ester which was used directly in the next step.
Example 408C (2S)-3-methyl-2-[({methyl[(2-methyl-l,3-thiazol-4- yl)methyl]ammo}carbonyl)amino]butanoic acid Example 408B (0.57 g) was dissolved in dioxane (8 mL) and freated with 1.4M LiOH (8 mL, in water) at 25 °C for 1 h. The mixture was quenched with iM HCI (4 mL), and the solvents were evaporated, and the residue was purified using 5% methanol/dichloromethane to give 0.52 g (96%) ofthe acid. The compounds listed in Table 9, wherein X13 and X7 represents the points of connection to the core structure (G), were prepared by coupling ofthe p-nifrophenyl carbamates ofthe conesponding amino acid methyl esters with the conesponding arylamines, heteroarylamines, and alkylamines by the procedures as exemplified in Example 406-408C.
Figure imgf000182_0001
(G) Table 9
Figure imgf000182_0002
Figure imgf000183_0001
Example 434 (2S,3S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-({[methyl(2- pyridinylmethyl)amino]carbonyl}amino)pentanamide Method A Example 421 (20 mg, 0.071 mmol ) is combined with HOBT (9.6 mg, 1.5 equivalent) and EDAC (14 mg, 1.5 equivalents) in N,N-dimethylformamide (1 mL) and stined for 1 h at 25° C. To this mixture is added N-methylmorpholine (NMM) (5.3 μL, 1 equivalent) and Example 18 (20 mg, 1 equivalent). The mixture is stined for 16 h, evaporated under vacuum, and purified by silica gel chromatography using 7% methanol/dichloromethane to give 13.4 mg (41%) ofthe title compound. Η NMR (300 MHz, CDC13) δ ppm 0.77 (m, 6 H), 0.83 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.97 (d, J=3.73 Hz, 1 H), 1.88 (m, J=6.78 Hz, 2 H), 2.85 (m, 2 H), 2.98 (m, 8 H), 3.07 (m, 2 H), 3.37 (dd, J=14.92, 4.75 Hz, 1 H), 3.85 (s, 1 H), 4.14 (m, 1 H), 4.22 (s, 2 H), 4.31 (d, J=15.60 Hz, 1 H), 7.18 (m, 5 H), 7.28 (s, 1 H), 7.70 (d, J=8.48 Hz, 2 H), 7.77 (s, 1 H), 7.82 (d, J=8.48 Hz, 2 H), 8.12 (s, 1 H), 8.20 (s, 1 H).
Example 435 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-( { [[(2-isopropyl- 1 ,3 - thiazol-4-yl)methyl](methyl)amino]carbonyl}amino)-3-methylbutanamide Method Ε Example 409 (activated as O-succinimide ester) (75 mg, 0.18 mmol) was dissolved in dichloromethane (1 mL) and Ν,Ν-dimethylformamide (0.5 mL) and freated with Example 18 (85 mg, 1.1 equivalents) and N-methylmorpholine(24.3 μL, 1.2 equivalents) at 25 °C for 16 h. The mixture was partitioned between dichloromethane and IN NaHCO3. The organic layer was separated, the solvents were evaporated, and the residue was purified using 4%> methanol/dichloromethane to give 70 mg (53%>) ofthe title compound. Η NMR (300 MHz, CD3OD) δ ppm 0.75 (d, J=3.05 Hz, 3 H), 0.78 (d, J=3.05 Hz, 3 H), 0.84 (d, J=6.78 Hz, 3 H), 0.89 (d, J=6.78 Hz, 3 H), 1.36 (d, J-6.44 Hz, 6 H), 1.92 (m, 2 H), 2.64 (dd, J=13.90, 10.51 Hz, 1 H), 2.94 (s, 3 H), 3.08 (m, 5 H), 3.14 (m, 1 H), 3.44 (dd, J=14.92, 3.39 Hz, 1 H), 3.79 (m, 1 H), 3.95 (d, J=7.46 Hz, 1 H), 4.06 (m, 1 H), 4.47 (t, J=16.28 Hz, 2 H), 7.10 (m, 3 H), 7.16 (s, 1 H), 7.20 (m, 2 H), 7.76 (d, J=8.48 Hz, 2 H), 7.82 (d, JN5.44 Hz, 2 H), 8.13 (s, 1 H). The compounds listed in Table 10, wherein X13, X7 and X3 represent respectively the points of connection to the core structure (H), were prepared by coupling the conesponding acids (Example 409-433) with the conesponding amines (Example 1-31) using the procedures as exemplified by Example 434 (Method A) or Example 435 (Method E .
Figure imgf000184_0001
Table 10
Figure imgf000184_0002
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Example 466 (2S,3R)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-hydroxy-2-({[{[2- (methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} (methyl)amino]carbonyl} amino)butanamide Example 444 (57 mg, 0.073 mmol) was freated with trifluoroacetic acid: dichloromethane (4 mL, 1 :1) at 25 °C for 1 h. The solvents were evaporated and the crude solid was triturated with ethyl acetate: hexanes 1:5 to give 53 mg (99%) ofthe title compound.
Example 467 (2S,3R)-N-{(lS,2R)-l-benzyl-3-[(cyclopentyhnethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-hydroxy-2-({[{[2- (methoxymethyl)-l,3-thiazol-4-yl]methyl}(methyl)amino]carbonyl}amino)butanamide Example 445 (41 mg, 0.051 mmol) was dissolved in dichloromethane: trifluoroacetic acid (4 mL, 1 : 1) at 25 °C for 1 h. The solvents were evaporated and the mixture was triturated with hexanes to precipitate 38 mg (100%) ofthe title compound.
Example 468 (2S,3S)-2-({[(3-aminobenzyl)(methyl)amino]carbonyl}amino)-N-{(lS,2R)-l-benzyl-2- hydroxy-3 - [( {4- [(E)-(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3- methylpentanamide Example 453 (19 mg, 0.026 mmol) was dissolved in ethyl acetate (1 mL) and treated with 10%) Pd/C (6 mg) at 25 °C for 3.5 h. The catalyst was filtered and the solvents were evaporated. The crade residue was purified using 5% methanol/chloroform to give 17 mg (94%>) ofthe title compound.
Example 469 (2S,3R)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)~ (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-hydroxy-2-[( {methyl[(2- methyl- 1 ,3 -thiazol-4-yl)methyl] amino } carbonyl) amino]butanamide Example 451 (25 mg) was dissolved in dichloromethane (2 mL) was freated with trifluoroacetic acid (2 mL) and stined at 25 °C for 1 h. The solvents were evaporated. The residue was partitioned with saturated ΝaHCO3 and chloroform, and the organic layer was dried over Na2SO4 and evaporated to give 20 mg (98%>) ofthe title compound. Example 470 (2S,3R)-N- {(1S,2R)- 1 -benzyl-3-[(cyclobutyhnethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-hydroxy-2- [({methyl[(2-methyl-l,3-thiazol-4-yl)methyl]amino}carbonyl)amino]butanamide Example 452 was freated in a similar manner as in Example 469 to give the title compound.
Example 471 (2S,3S)-2-( { [ {[2-(aminomethyl)- 1 ,3 -thiazol-4-yl]methyl} (methyl)amino]carbonyl} amino)-N- {(1S,2R)~ 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methylpentanamide
Example 471 A tert-butyl 2-amino-2-thioxoethylcarbamate Boc-glycine (2.34 g, 0.134 mmol) was dissolved in dichloromethane (130 mL) and treated with Lawesson's reagent (2.9 g, 0.52 equivalents) and the mixture was stined at 25 °C for 16 h. The mixture was filtered and the solvents were evaporated. The residue was purified using dichloromethane: ethyl acetate (1:1) to give 2.56 g (100%>) ofthe thioamide.
Example 47 IB tert-butyl {4-[(methylamino)methyl]- 1 ,3-thiazol-2-yl}methylcarbamate Example 471A (0.5 g) was dissolved in isopropanol (10 mL) and treated with dichloroacetone (0.33 g, 1 equivalent) and the mixture was stined at 25 °C for 16 h. The solvents were evaporated, and the crade residue was dissolved in isopropanol (2 mL) and treated with 40% methylamine in water (5 mL, 25 equivalents). The solvents were evaporated, and the residue was partitioned between ethyl acetate and sat ΝaHCO . The organic layer was separated, dried over MgSO4, filtered, and the solvents were evaporated to give 0.48 g ofthe title compound.
Example 47 IC methyl (2S,3S)-2-( { [[(2- {[(tert-butoxycarbonyl)amino]methyl} -1 ,3-thiazol-4- yl)methyl](methyl)amino]carbonyl}amino)-3-methylpentanoate Example 47 IB (0.48 g) was dissolved in tetrahydrofuran (10 mL) and freated with triethyl amine (0.78 mL, 3 equivalent), DMAP (34 mg, 15mol%) followed by Example 406 (0.7 g, 1.2 equivalent) and the mixture was heated to 66 °C for 16 h. The mixture was partitioned between ethyl acetate and saturated NaHCO , the organic layer was separated, washed with brine and dried over MgSO4, filtered, and the solvents were evaporated. The residue was purified using ethyl acetate to give 0.37 g (46%>) ofthe title compound. _ __
Example 47 ID (2S,3S)-2-( {[[(2- { [(tert-butoxycarbonyl)amino]methyl} - 1 ,3 -thiazol-4- yl)methyl](methyl)amino]carbonyl} amino)-3-methylpentanoic acid Example 47 IC (0.37 g) was dissolved in tefrahydrofuran: water (4 mL, 3:1) and freated with LiOH (0.11 g, 3 equivalents) and the mixture was stined at 25 °C for 30 min. The mixture was quenched with IN HCI (2.75 mL) and partitioned between ethyl acetate and brine, the organic layer was separated, dried over MgSO4, filtered, and the solvents were evaporated to give 0.36 g (100%) ofthe crude acid.
Example 471E tert-butyl (4-{(5S,8S,9R)-8-benzyl-9-hydroxy-l l-({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)-2,13-dim 2,4,7, 11 -tefraazatetradec- 1 -yl} - 1 ,3-thiazol-2-yl)methylcarbamate Example 47 ID (35 mg) was dissolved in N,N-dimethylformamide (0.85 mL) and treated with EDAC (25 mg, 1.5 equivalents), HOBT (17 mg, 1.5 equivalents), N- methylmorpholine(10 μL, 1.1 equivalents) followed by Example 18 (35 mg, 1 equivalent), and the mixture was stined at 25 °C for 16 h. The solvents were evaporated and the residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%>) to give 74 mg (100%>) ofthe title compound.
Example 47 IF tert-butyl (4-{(5S,8S,9R)-8-benzyl-9-hydroxy-l l-({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)-2,13-dimethyl-5-[(lS)-l-methylpropyl]-3,6-dioxo- 2,4,7,1 l-tetraazatefradec-l-yl}-l,3-thiazol-2-yl)methylcarbamate Example 47 IE was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) and stined at 25 °C for 30 min. The solvents were evaporated, and the residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid):acetonitrile (95:5) to acetonitrile (100%) to give 61 mg (81%>) ofthe title compound.
Example 472
(2S,3S)-2-({[{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}(methyl)amino]carbonyl}amino)-N- {(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methylpentanamide Example 472 was prepared as for Example 471F using Example 471D and Example
19 followed by deprotection as in Example 47 IF to give the title compound. Example 473
(2S,3S)-2-({[{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}(methyl)amino]carbonyl}amino)-N- {(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methylpentanamide Example 473 was prepared as for Example 471F using Example 471D and Example
27 followed by deprotection as in Example 47 IF to give the title compound.
Example 474 [ (2S,3S)-2-({[({2-[(lS)-l-aminoethyl]-l,3-thiazol-4- yl}methyl)(methyl)amino]carbonyl}amino)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3- methylpentanamide
Example 474A tert-butyl ( 1 S)-2-amino- 1 -methyl-2-oxoethylcarbamate To a solution containing Boc-Z-alanine (1.0 g, 5.29 mmol) in a mixture of tefrahydrofuran (25 mL) and Ν,Ν-dimethylformamide (5 mL) were added EDAC (1.5 g, 7.82 mmol) and N-hydroxysuccinimide (0.91 g, 7.91 mmol) and the mixture was stined at room temperature for 16 hours. Aqueous ammonium hydroxide solution (15 mL, 28%>) was added and the mixture was stined for 0.5 hours at room temperature. The reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give the product (0.483 g, 49%> yield), which was used without further purification. Example 474B tert-butyl (15)-2-amino-l -methyl-2-thioxoethylcarbamate To Example 474A (0.48 g, 2.55 mmol) in dichloromethane (25 mL) was added Lawesons Reagent (0.54 g, 1.34 mmol), and the mixture was stined at room temperature for 16 hours. The solvent was evaporated and the residue was purified using dichloromethane - 35%o ethyl acetate in dichloromethane to give the product (0.52 g, 100%) yield).
Example 474C ethyl 2-{(lS)-l-[(tert-butoxycarbonyl)amino]ethyl}-l,3-thiazole-4-carboxylate To Example 474B (0.914 g, 4.48 mmol) in DME (7 mL) at -20 °C were added pulverized KHCO (3.55 g, 35.46 mmol) and ethyl bromopyravate (1.65 mL, 13.15 mmol), and the mixture was stined at -20 °C for 1 hour. A solution of trifluoroacetic anhydride (2.5 ml, 17.70 mmol) and 2,6-lutidine (4.4 mL, 37.78 mmol) in dimethylether ( 4.5 mL) was added to the reaction at -20 °C and the reaction was stined at that temperature for 2 hours. The reaction was poured into water and was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated. The residue was purified using dichloromethane - 15%o ethyl acetate in dichloromethane to give the product (1.26 g, 94% yield).
Example 474D tert-butyl (lS)-l-{4- [(methylamino)methyl] - 1 ,3 -tlιiazol-2-yl} ethylcarbamate To Example 474C (0.50 g, 1.67 mmol) in a mixture of tetrahydrofuran (15 mL) and methanol (1 mL) was added LiBH4 (0.15 g, 6.89 mmol) and the mixture was stined at room temperature for 5 hours. The reaction was partitioned between dichloromethane and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated. To a solution of this product (1.67 mmol) were added triethylamine (0.70 mL, 5.02 mmol) and methanesulfonyl chloride (0.195 mL, 2.52 mmol) at 0 °C and the reaction was stined at this temperature for 0.5 hours. The reaction was partitioned between dichloromethane and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give the crude mesylate. To an aqueous solution of methylamine (5 mL, 40%) was added a solution ofthe mesylate (1.67 mmol) in 2-propanol (2 mL) and the mixture was stined at room temperature for 1.5 hours. The solvent was removed under reduced pressure to give the product (0.305 g), which was used without further purification.
Example 474F methyl (2S,3S)-2-( { [[(2- {( IS)- 1 -[(tert-butoxycarbonyl)amino] ethyl} - 1 ,3 -thiazol-4- yl)methyl](methyl)amino]carbonyl}amino)-3-methylpentanoate Example 474D (0.305 g, 1.13 mmol) was dissolved in tefrahydrofuran (6 mL) and freated with Example 406 (0.525 g, 1.69 mmol), triethylamine (0.47 mL, 3.37 mmol), and DMAP (0.020 g, 0.16 mmol), at room temperature and the mixture was stined at 80 °C for 16 hours. The reaction was cooled and partitioned between ethyl acetate and saturated NaHCO3, and the organic was washed with brine and dried over MgSO4, filtered and evaporated. The residue was purified using dichloromethane - ethyl acetate to give the product (0.344 g, 69% yield).
Example 474G (2S,3S)-2-({[[(2-{(lS)-l-[(tert-butoxycarbonyl)amino]ethyl}-l,3-thiazol-4- yl)methyl](methyl)amino]carbonyl}amino)-3-methylpentanoic acid To Example 474F (0.344 g, 0.778 mmol) in dioxane (3 mL) was added an aqueous solution of lithium hydroxide (3.0 mL, 0.5 M), and the reaction was stined for 0.5 hours at room temperature. Aqueous HCI (1.62 mL, 1 N) was added and the reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give the product, which was used without further purification.
Example 474H tert-butyl (lS)-l-(4-{(5S,8S,9R)-8-benzyl-12-cyclopentyl-9-hydroxy-ll-({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)-2-methyl-5-[(lS)-l-methylpropyl]-3,6-dioxo- 2,4,7, 11 -tefraazadodec- 1 -yl} - 1 ,3 -thiazol-2-yl)ethylcarbamate Example 474G (35 mg) was dissolved in N,N-dimethylformamide (0.85 mL) and treated with EDAC (25 mg, 1.5 equivalents), HOBT (17 mg, 1.5 equivalents), N- methylmorpholine(10 μL, 1.1 equivalents) followed by Example 27 (35 mg, 1 equivalent), and the mixture was stined at 25 °C for 16 h. The solvents were evaporated and the residue was purified by HPLC reverse phase chromatography using water (0.1 % trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 74 mg (100%) ofthe title compound.
Example 4741 (2S,3S)-2-( {[( {2-[(lS)-l -aminoethyl]- 1 ,3-thiazol-4- yl}methyl)(methyl)amino]carbonyl}amino)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4- [(E)-(hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -3- methylpentanamide Example 474H was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) and stined at 25 °C for 30 min. The solvents were evaporated, and the residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 61 mg (81%) ofthe title compound.
Example 475 (2S,3S)-2-({[({2-[(lR)-l-aminoethyl]-l,3-thiazol-4- yl}methyl)(methyl)amino]carbonyl} amino)-N- {(1 S,2R)- 1 -benzyl-3 -[(cyclopentylmethyl)( {4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3- methylpentanamide In a similar manner to Example 474 but starting with Boc-(D)-alanine, Example 475 was prepared via coupling and deprotection. Example 476 (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -2-( {[( {6-[N- hydroxyethanimidoyl]-2-pyridinyl}methyl)(methyl)amino]carbonyl}amino)-3- methylpentanamide
Example 476A 1 -[6-(hydroxymethyl)-2-pyridinyl]ethanone The title compound was prepared according to the procedure as described in Katsura, Y. et. al., Journal of Medicinal Chemistry, 37, 57-66 (1994).
Example 476B 1 - [6-(chloromethyl)-2-pyridinyl] ethanone To Example 476A (0.23 g, 1.52 mmol) in N,N-dimethylformamide (2 mL) at 0°C was treated phosphorus oxychloride (0.283 mL, 3.04 mmol). The mixture was stined 3 hours at 0°C, quenched with IM sodium bicarbonate, and extracted with ethyl acetate. The organic layer was evaporated, and the residued was purified using 10% ethyl acetate / hexane to give 86 mg (33.4%) of the title compound.
Example 476C l-{6-[(methylamino)methyl]-2-pyridinyl}ethanone Example 476B (86 mg, 0.5 mmol) at 25°C was treated with 2 M methylamine in tetrahydrofuran (2 mL, 4 mmol). The reaction was stined at 25°C for 16 hour, the solvent was concentrated and the residue was purified using 10% methanol/dichloromethane with 0.5%) ammonium hydroxide to give 53 mg (72.6%) ofthe title compound.
Example 476D tert-butyl (2S,3S)-2-({[[(6-acetyl-2-pyridinyl)methyl](methyl)amino]carbonyl}amino)-3- methylpentanoate To Example 476C (50 mg, 0.3 mmol), Example 406 (107 mg,0.3 mmol) in N,N- dimethylformamide (2 mL) at 25 °C was treated with diisopropylethylamine (64 μL, 0.36mmol) followed by N,N-dimethylaminopyridine (5.2 mg, 0.042 mmol). The mixture was stined for 16 hour, quenched with IM sodium bicarbonate, and exfracted with ethyl acetate. The organic layer was evaporated, and the residued was purified using 30% ethyl acetate/hexane to give 97 mg (84.4%) ofthe title compound.
Example 476E (2S,3S)-2-({[[(6-acetyl-2-pyridinyl)methyl](methyl)amino]carbonyl}amino)-3- methylpentanoic acid Example 476D (97 mg, 0.257 mmol) at 25°C was freated with 80% trifluoroacetic acid in dichloromethane (1.5 mL). The reaction was stined at 25°C for 3 hour, the solvent was concentrated and the residue was dissolved in water (0.5 mL) and purified using 7% methanol/dichloromethane to give 100 mg (89.3%.) ofthe title compound.
Example 476F (2S,3S)-2-({[[(6-acetyl-2-ρyridinyl)methyl](methyl)amino]carbonyl}amino)-N-{(lS,2R)-l- benzyl-3-[(cyclopentylmethyl)({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2- hydroxypropyl} -3 -methylpentanamide Example 476E (99 mg, 0.31 mmol) was dissolved in Ν,Ν-dimethylformamide (3 mL) and combined with EDAC (88 mg, 1.5 equivalents), HOBT (62 mg, 1.5 equivalents), and N- methylmorpholine(34 μL, 1 equivalent) followed by addition of Example 27 (164 mg, 1.2 equivalents). The mixture was stined for 4 d at 25 °C, quenched with IN NaHCO , and exfracted with ethyl acetate. The solvents were evaporated and the residue was purified using 5% methanol/dichloromethane to give 84 mg (47%>) ofthe ketone.
Example 476G (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-({[({6-[N- hydroxyethanimidoyl]-2-pyridinyl}methyl)(methyl)amino]carbonyl}amino)-3- methylpentanamide Example 476F (75 mg) was dissolved in methanol (2 mL) and combined with hydroxylamine hydrochloride (14 mg, 2 equivalents). The mixture was stined at 25 °C for 16 h. The solvents were evaporated and the residue was purified using 10% methanol/dichloromethane to give 54 mg (70%») ofthe title compound.
Example 477 (2S,3S)-2-({[({2-[(lS)-l-(acetylamino)ethyl]-l,3-thiazol-4- yl}methyl)(methyl)amino]carbonyl}amino)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4- [(E)-(hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -3- methylpentanamide Example 4741 (0.87 g) was dissolved in dichloromethane (0.2 mL) and treated with triethyl amine (3.2 μL, 2 equivalents) and acetic anhydride (1.3 μL, 1.2 equivalents), and the mixture was stined at 25 °C for 3 h. The solvents were evaporated, and the residue was purified by HPLC reverse phase chromatography using water (0.1%> trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 11.3 mg (100%>) ofthe title compound. Example 478 tert-butyl (1S)-1 -[( {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2,2- dimethylpropylcarbamate Method D (L)-Boc-t-leucine (55 mg, 0.024 mmol) was dissolved in tefrahydrofuran (10 mL) and treated with triethyl amine (66 μL, 2 equivalents), 3-(diethylphosphoryloxy)- 1,2,3- benzotriazin-4(3H)-one (DEPBT) (86 mg, 1.2 equivalents), and Example 18 (0.1 g, 1 equivalent) at 25 °C for 16 h. The mixture was partitioned between ethyl acetate and 10% Na2CO3, the organic layer was separated, washed with water, brine, dried over Na So4, and the solvents were evaporated. The residue was purified using ethyl acetate: hexanes (1 :2) to give 0.114 g (76%) ofthe title compound. Η NMR (300 MHz, CDC13) δ ppm 0.87 (m, 15 H), 1.42 (s, 9 H), 1.85 (m, 1 H), 2.84 (m, 1 H), 2.95 (m, 1 H), 3.02 (m, 1 H), 3.13 (m, 1 H), 3.69 (d, J=8.46 Hz, 1 H), 3.85 (m, 2 H), 4.12 (q, J=7.11 Hz, 1 H), 4.19 (m, 1 H), 4.94 (s, 1 H), 6.00 (d, J=8.46 Hz, 1 H), 7.22 (m, 5 H), 7.70 (d, J=8.82 Hz, 2 H), 7.76 (d, J=8.46 Hz, 2 H), 8.16 (s, 1 H). ) Example 479 hexahydrofuro[2,3-b]furan-3-yl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate
Example 479A hexahydrofuro[2,3-b]furan-3-yl 4-nifrophenyl carbonate To a solution of (3S,3aR,6aS)- and (3R,3aS,6aR)-3-hydroxy-4H-hexahydrofuro[2,3- b]furan (see compound 15 in: Gosh, A.K.; Kincaid, j. F.; Walters, D. E.; Chen, Y.;
Chaudhuri, N. C; Thompson, W. J.; Culberson, C; Fitzgerald, P. M. D.; Lee. H. Y.; McKee, S. P.; Munson, P. M.; Duong, T. T.; Darke, P. L.; Zugay, J. A.; Schleif, W. A.; Axel, M. G.; Lin, j.; Huff, j. R. Journal of Medicinal Chemistry 1996, 39, 3278-3290.) (1.5 g, 11.5 mmol) in dichloromethane (40 mL) at 0 °C were added N-methylmorpholine( 1.9 mL, 17.3 mmol) and 4-nitroρhenyl chloroformate (2.9 g, 14.4 mmol), and the mixture was stined for 16 hours at 0 °C. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel, eluting with 25% ethyl acetate in hexanes to give the product (2.91 g, 86% yield). Example 479B hexahydrofuro[2,3-b]furan-3-yl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate Method F Example 479 A (10.6 mg, 0.036 mmoles, 1.5 equivalents) was combined with Example 18 (10 mg, 0.024 mmoles) in tetrahydrofuran (0.5 mL) at 25 °C for 24 h. The solvent was evaporated under vacuum, and the residue was purified using 2% methanol/dichloromethane to give 10.9 mg (80% yield) ofthe title compound. Η NMR (300 MHz, CDC13) δ ppm 0.87 (dd, J=6.44, 3.73 Hz, 3 H), 0.93 (m, 3 H), 1.84 (s, 2 H), 2.85 (m, 2 H), 3.01 (m, 3 H), 3.16 (m, 1 H), 3.59 (dd, J=9.66, 6.61 Hz, 1 H), 3.69 (m, 1 H), 3.85 (m, 3 H), 3.96 (m, 2 H), 4.93 (dd, J=16.95, 8.14 Hz, 1 H), 5.01 (s, 1 H), 5.66 (m, 1 H), 7.27 (m, 5 H), 7.55 (d, J=2.03 Hz, 1 H), 7.72 (d, J=8.48 Hz, 2 H), 7.78 (m, 2 H), 8.16 (s, 1 H). The compounds listed in Table 11, wherein X and X5 represent respectively the points of connection to the core structure (I), were prepared by coupling available activated acids and carbonates with Examples 1-31 as exemplified in Example 434 (Method A) or
Example 162 (Method B), Example 435 (Method E), or Example 479 (Method F).
Figure imgf000197_0001
Table 11
Figure imgf000197_0002
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Example 513 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-({[(3- fluorobenzyl)amino]acetyl}amino)-3,3-dimethylbutanamide
Example 513A methyl (2S)-2-[(chloroacetyl)amino]-3,3-dimethylbutanoate (L)-methyl t-leucinate hydrochloride (1 g) was dissolved in ethyl acetate (6 mL) and water (4 L) and freated with K2CO3 (1.66 g, 3 equivalents) followed by chloroacetyl chloride (0.53 mL, 1.2 equivalents) at 25 °C for 2 h. The organic layer was separated, washed with 10% citric acid, and the solvents were evaporated. The residue was purified by ethyl acetate: hexanes (1:4) to give 1.22 g (100%) ofthe chloro ester. Example 513B methyl (2S)-2-({[(3-fluorobenzyl)amino]acetyl}amino)-3,3-dimethylbutanoate Example 513A (1.22 g) was dissolved in tetrahydrofuran (5 mL) and treated with 3- fluorobenzyl amine (1.9 mL, 3 equivalents) at 60 °C for 16 h. The solvents were evaporated and the residue partitioned between IN ΝaHCO3 and ethyl acetate. The organic layer was separated and purified using ethyl acetate: hexanes (3:2) to give 1.22 g (71 >) ofthe title compound.
Example 513C methyl (2S)-2-({[(tert-butoxycarbonyl)(3-fluorobenzyl)amino]acetyl}amino)-3,3- dimethylbutanoate Example 513B (1.22 g) was dissolved in dioxane (14 mL) and treated with IN NaHCO3 (9 mL, 2.3 equivalents) followed by Boc2O (1.11 g, 1.3 equivalents) at 25 °C for 16 h. The mixture was partitioned between water and ethyl acetate, the organic layer separated, and the solvents were evaporated. The residue was purified using ethyl acetate: hexanes (1 :4) to give 1.55 g (96%) ofthe protected amine.
Example 513D 2-({[(tert-butoxycarbonyl)(3-fluorobenzyl)amino]acetyl}amino)-3,3-dimethylbutanoic acid Example 513C (1 g) was dissolved in tetrahydrofuran (6 mL) and treated with LiOH (0.133 g, 1.3 equivalents) in water (3 mL) at 0 °C for 16 h. The solvents were evaporated, and the residue was partitioned between water and ethyl acetate. The aqueous layer was separated, acidified with 10% citric acid to pH 2-3, and extracted with ethyl acetate. The organic layer was separated, and the solvents were evaporated. The residue was purified using 10%) methanol/dichloromethane to give 0.9 g (93%>) ofthe acid as epimers at the alpha center which were not separable.
Example 513E tert-butyl 2-({(lS)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2,2- dimethylpropyl}amino)-2-oxoethyl(3-fluorobenzyl)carbamate Example 513D (0.125 g) was dissolved in N,N-dimethylformamide (2 mL) and freated with EDAC (82 mg, 1.5 equivalents), HOBT (58 mg, 1.5 equivalents), followed by Example 18 (0.12 g, 0.9 equivalent) at 25 °C for 3 d. The mixture was partitioned between IN NaHCO3 and ethyl acetate. The organic layer was separated, and the solvents were evaporated. The residue was separated using ethyl acetate: hexanes (1:1) to give 0.21 g of Example 514E and 0.36 g of Example 513E. Example 513F (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-({[(3- fluorobenzyl)amino]acetyl} amino)-3,3-dimethylbutanamide Example 513E (0.105 g) was dissolved in 80%> trifluoroacetic acid (3 mL) at 25 °C for 2 h. The solvents were evaporated, and the residue was purified using 10% methanol/ethyl acetate w/0.5% ΝH OH to give 53 mg (58%) ofthe title compound.
Example 514 (2R)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-({[(3- fluorobenzyl)amino]acetyl}amino)-3,3-dimethylbutanamide
ΕXample 514Ε tert-butyl 2-({(lR)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} amino)carbonyl]-2,2- dimethylpropyl} amino)-2-oxoethyl(3 -fluorobenzyl)carbamate Example 514F (2R)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-({[(3- fluorobenzyl)amino] acetyl} amino)-3 ,3 -dimethylbutanamide Example 514E (0.11 g) was deprotected as for Example 513F to give 74 mg (81%.) of the title compound.
Example 515 (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-({[(3- fluorobenzyl)amino]acetyl}amino)-3-methylpentanamide
Example 515 A N-Boc-glycyl-(L)-isoleucine (0.5 g) was dissolved in tetrahydrofuran (25 mL) and freated with Boc2O (0.64 g, 1.1 equivalents) and IN ΝaOH (2.66 mL, 1 equivalent) at 25 °C for 2 h. The mixture was partitioned between ΝaHCO3 and dichloromethane. The aqueous layer was separated, acidified with 10%» citric acid, and exfracted with dichloromethane. The organic layer was separated, dried with MgSO4, filtered, and the solvents were evaporated to give 0.3 g (39%) ofthe Boc compound.
Example 515B tert-butyl 2-({(lS,2S)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- methylbutyl}amino)-2-oxoethylcarbamate Example 515A (34 mg) was dissolved in N,N-dimethylformamide (3 mL) and treated with EDAC (25 mg, 1.1 eq), HOBT (18 mg, 1.1 equivalents), and Example 18 (50 mg, 1 equivalent) at 25 °C for 16h. The mixture was partitioned dichloromethane and IN NaHCO3, the organic layer was separated, dried over MgSO4, and the solvents were evaporated. The residue was purified using ethyl acetate: hexanes (2:1) to give 67 mg (82%>) of the amide.
Example 515C (2S,3S)-2-[(aminoacetyl)amino]-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide Example 515B (0.44 g) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (8 mL) at 25 °C for 2.5 h. The solvents were evaporated, and the residue was dissolved in dichloromethane, washed with 0.5N NH4OH, dried with MgSO4, filtered, and the solvents were evaporated to give 0.378 g (100%>) ofthe title compound.
Example 515D (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-( { [(3 - fluorobenzyl)amino]acetyl}amino)-3-methylpentanamide Example 515C (12 mg) was dissolved in methanol (1 mL) and benzene (1 mL) and freated with 3-fluorobenzaldehyde (2.2 μL, 1 equivalent), and this mixture is heated to 50 °C for 1.5 h. The mixture is cooled and treated with ΝaBH4 (3.8 mg, 5 equivalentss) at 25 °C for 1 h. The mixture was quenched with water and dichloromethane, the organic layer was separated, dried with MgSO4, filtered, and the solvents were evaporated. The residue was purified using ethyl acetate with 1% NH4OH to give 4.7 mg (33%) ofthe title compound.
Example 517 (2S,3S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[({[(5-nifro-3- thienyl)methyl] amino } acetyl)amino]pentanamide In a similar manner to Example 515D, the title compound was prepared by coupling 2-nifrothiophene-3-carboxaldehyde with Example 515C.
Example 518 benzyl (lS)-4-{[amino(imino)methyl]amino}-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]butylcarba mate
Example 518A benzyl (15)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-4-[((Z)- [(tert-butoxycarbonyl)amino]{[(Z)-tert-butoxycarbonyl]imino}methyl)amino]butylcarbamate Z-Arginine(Boc)2OH cyclohexylamine salt (22 mg) was dissolved in water, acidified with 10%) citric acid and exfracted with ethyl acetate. The organic layer was separated, dried over Na SO4, and the solvents were evaporated to give the free acid. This acid was dissolved in N,N-dimethylformamide (0.5 mL) and treated with ΕDAC (13.7 mg, 1.5 equivalents), HOBT (9.66 mg, 1.5 equivalents), and N-methylmorpholine(5.3 μL, 1 equivalent) followed by the Example 18 (20 mg, 1 equivalent) at 25 °C for 2 d. The mixture was partitioned between IN NaHCO3 and ethyl acetate. The organic layer was separated, and the solvents were evaporated. The residue was purified using 5% ethyl acetate/hexanes to give 21 mg (48%) ofthe di-Boc compound.
Example 518B benzyl (lS)-4-{[amino(imino)methyl]amino}-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]butylcarba mate Example 518A (21 mg) was dissolved in 80%> trifluoroacetic acid (1 mL) at 25 °C for
2 h. The solvents were evaporated and purified by preparative TLC using 0.25mm plates and 8% methanol/dichloromethane/1% NH4OH to give 9 mg (55%>) ofthe title compound.
Example 519 (2S)-2-amino-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethylbutanamide Example 478 was freated with trifluoroacetic acid as for Example 518B to give the title compound. Example 520 N-{(2R,3S)-2-hydroxy-3-[({4-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-4- phenylbutyl}-4-[(E)-(hydroxyimino)methyl]-N-isobutylbenzenesulfonamide
Example 520A (acetyloxy){4-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)-
(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} amino)sulfonyl]phenyl} met hyl acetate Example 18 (78.6 mg) was dissolved in tefrahydrofuran (1 mL) and Ν,Ν- dimethylformamide (0.1 mL) and freated with the product of Example 17 from Part 1 of Method B, (70.5 mg, 1.2 equivalents) and triethyl amine (78 μL, 3 equivalents) at 25 °C for 2 h. The solvents were evaporated, and the residue was purified using dichloromethane to give 87 mg (68%ι) ofthe sulfonamide.
Example 520B N-{(2R,3S)-2-hydroxy-3-[({4-[(hydroxyimino)methyl]phenyl}sulfonyl)amino]-4- phenylbutyl}-4-[(E)-(hydroxyimino)methyl]-N-isobutylbenzenesulfonamide Example 520A (87 mg) was dissolved in ethanol (1.2 mL) and treated with hydroxylamine hydrochloride (19 mg, 1.5 equivalents) and triethyl amine (91 μL, 3.5 equivalents) at 75 °C for 1 h. The solvents were evaporated, and the residue was purified using dichloromethane to give 88 mg (100%>) ofthe title compound.
Example 521 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide
Example 521A tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propylcarbamate To a solution of (2R,3S)-3-Ν-tert-butoxycarbonylamino-l,2-epoxy-4-phenylbutane (0.2 g, 0.76 mmol) in 2-propanol (4 mL) was added the isobutylamme (1.5 mL, 20 equivalents), and the mixture was heated at 80 °C for 2 hours. The solvents were evaporated, and the crude residue was dissolved in dichloromethane (8 mL) and treated with triethylamine (0.32 mL, 3 equivalents) and p-methoxybenzenesulfonyl chloride (0.173 g, 1.1 equivalents) and the mixture is stined at 25 °C for 1 h. The solvents were evaporated and the crude, residue was purified using 0.5%> methanol/dichloromethane to give 0.356 g (92%) of the title compound.
Example 52 IB N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide Example 521 A (47 mg, 0.093 mmol) was dissolved in trifluoroacetic acid: dichloromethane (4 mL, 1:1) at 25 °C for 1 h. The solvents were evaporated to give 38 mg (100%) ofthe title compound. The compounds listed in Table 12, wherein X3 represents respectively the points of connection to the core structure (J), were prepared by the procedures as exemplified in Example 521A and Example 521B, substituting cyclopentylmethylamine and neopentylamine, respectively, for isobutylamme.
Figure imgf000206_0001
Table 12
Figure imgf000206_0002
Figure imgf000207_0001
Example 524 (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 2-{3-[(2-isopropyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylbutanamide Method C Example 144 (25 mg ) was combined with Ν-hydroxysuccinimide (10 mg, 1.1 equivalents) and DCC (18 mg, 1.1 equivalents) in dichloromethane (1 mL) and stined for 1 h at 25° C. The solids are filtered, and to this mixture was added Ν-methyhno holine (9 μL, 1 equivalent) and Example 52 IB (31 mg, 1 equivalent). The mixture was stined for 16 h, evaporated, and was purified using 1%. methanol/chloroform to give 33 mg (60%) ofthe title compound. Η ΝMR (300 MHz, DMSO-d6) δ ppm 0.69 (dd, J=10.51, 6.44 Hz, 3 H), 0.81 (dd, J=6.61, 2.88 Hz, 3 H), 1.30 (d, J=2.37 Hz, 3 H), 1.32 (d, J=2.37 Hz, 3 H), 1.94 (m, 1 H), 2.40 (dd, J=13.73, 11.02 Hz, 1 H), 3.04 (m, 6 H), 3.28 (s, 3 H), 3.40 (m, 1 H), 3.61 (s, 1 H), 3.75 (d, J=10.85 Hz, 1 H), 3.83 (s, 3 H), 3.87 (s, 1 H), 4.02 (s, 2 H), 4.30 (d, J=15.60 Hz, 1 H), 4.39 (d, J=13.22 Hz, 1 H), 4.43 (d, J=7.80 Hz, 1 H), 4.93 (d, J=6.44 Hz, 1 H), 5.56 (d, J=7.80 Hz, 2 H), 7.07 (m, 7 H), 7.24 (s, 1 H), 7.71 (d, J=8.82 Hz, 2 H), 7.86 (d, J=9.49 Hz, 1 H). The compounds listed in Table 13, wherein X9j X7; and X3 represent respectively the points of connection to the core structure (J), were prepared by coupling the conesponding acids (Examples 32-160) with the conesponding amines ( Examples 521-523) as exemplified in Example 362 (Method A) or Example 161 (Method B), Example 524 (Method C) and
Figure imgf000207_0002
Tabl 13
Figure imgf000207_0003
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Example 587 (2S)-2-(3-{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N-((lS,2R)-l- benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylbutanamide
Example 587A tert-butyl (2S)-2-(3-{[2-(hydroxymethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)- 3-methylbutanoate Example 273D (509 mg) was dissolved in ethanol (14 mL) added ΝaBH4 (57.6 mg, 1.1 equivalents). The mixture was stined at 25 °C for 3 h and quenched with sat. NH C1 and the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over MgSO4. The solvents were evaporated to give 452 mg (88%o) crade alcohol.
Example 587B tert-butyl (2S)-3-methyl-2-{3-[(2-{[(methylsulfonyl)oxy]methyl}-l,3-thiazol-4-yl)methyl]-2- oxo- 1 -imidazolidinyl}butanoate Example 587 A (452 mg) was dissolved in dichloromethane (12 mL) added triethylamine (683 μL, 4 equivalents), cooled to 0 °C and methanesulfonyl chloride (190 μL, 2 equivalents). After 30 min. the solvents were evaporated. The residue was partitioned between ethyl acetate and 10% citric acid solution. The organic layer was separated and washed with 10% NaHCO3, brine, dried over MgSO4, filtered, and the solvents were evaporated to give 335 mg (61%>) of the title compound.
Example 587C (2S)-2-(3-{[2-(azidomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-3- methylbutanoic acid Example 587B (335 mg) was dissolved in N,N-dimethylformamide (5 mL) and LiN3 (366 mg, 10 equivalents) and the mixture was heated to 50 °C for 2.5 h. The solvents were evaporated and partitioned between ethyl acetate and brine, and the organic layer was separated, dried over MgSO4, filtered, and concentrated to give 292 mg of crade azide. The crude azide was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) and stined at 25 °C for 2 h. The solvents were evaporated to give 244 mg (96%) acid.
Example 587D (2S)-2-(3-{[2-(azidomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N-((lS,2R)-l- benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylbutanamide Example 587C (244 mg) was dissolved in Ν,Ν-dimethylformamide (7 mL) and HOBT (146 mg, 1.5 equivalents) , EDAC (168 mg, 1.5 equivalents), triethylamine (0.2 mL, 2 equivalents) followed by Example 521B (352 mg, 1.2 equivalents). The mixture was stined at 25 °C for 16 h. The solvents were evaporated, and the residue was purified using dichloromethan: ethyl acetate (100:0 to 0:100) to give 333 mg (64%) ofthe azide.
Example 587E (2S)-2-(3-{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N-((lS,2R)-l- benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylbutanamide Example 587D (270 mg, 0.37 mmol) was dissolved in tetrahydrofuran (3 mL) and water (0.7 mL) followed by triphenylphosphine (TPP) (195 mg, 2 equivalents). The mixture was heated to 50 °C for 1 h. The mixture was partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried over MgSO4 and the solvents were evaporated. The residue was purified using dichloromethane: ethyl acetate (1:1 to 100:0 to 10%) methanol/dichloromethane) to give 215 mg (83%>) ofthe title compound. Example 588 (2S)-2-[3-({2-[(acetylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]-N- ((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylbutanamide Example 587E (11 mg, 0.016 mmol) was dissolved in dichloromethane (0.15 mL) and treated with acetic anhydride (2.2 μL, 1.5 equivalents) and triethylamine (6.6 μL, 3 equivalents) at 25 °C for 1 h. The mixture was quenched with citric acid and washed with 10%) ΝaHCO3, brine, dried over MgSO4, filtered, and the solvents were evaporated. The residue was purified using dichloromethane:methanol (100:0 to 95:5) to give 9.8 mg (84%) of the title compound.
Example 589 (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- ' 2-(3-{[2-(hydroxymethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-3- methylbutanamide Example 550 (45 mg, 0.062 mmol) was dissolved in tetrahydrofuran: water (1 mL,
2:1) and treated with LiOH (8 mg) at 25 °C for 30 min. The mixture is quenched with IN HCI (0.2 mL) and partitioned between ethyl acetate and water, the organic layer is separated, washed with brine and dried over MgSO4, filtered, and the solvents were evaporated to give 43 mg (100%)) ofthe. title compound.
Example 590
(2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 2-[3-({2-[(dimethylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]-3- methylbutanamide Example 587E (50 mg, 0.071 mmol) was dissolved in acetonitrile (0.7 mL) added formaldehyde (27 μL, 5 equivalents) acetic acid (8.1 μL, 2 equivalents), ΝaCΝBH3 (9 mg, 2 equivalents). The mixture was stined at 25 °C for 3 h. The solvents were evaporated and the residue was purified using dichloromethane: methanol (95:5) to give 9 mg (17%>) ofthe title compound.
Example 591
(2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 3-methyl-2-{3-[(2-{[(methylsulfonyl)amino]methyl}-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl} butanamide Example 587E (16.5 mg, 0.023 mmol) was dissolved in dichloromethane (0.25 mL) and treated with mesyl chloride (2 μL, 1.1 equivalents) and triethylamine (9.8 μL, 3 equivalents) at 0 °C for 1 h. The solvents were evaporated and the residue was purified using 5% methanol/dichloromethane to give 12 mg (66%) ofthe title compound.
Example 592 (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 2-[3-({2-[(hydroxyimino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]-3- methylbutanamide Example 587E (10.2 mg, 0.0145 mmol) was dissolved in dichloromethane (0.2 mL) at 0 °C was treated with m-chloroperbenzoic acid (7 mg, 2 equivalents) and the mixture was stined for 2 h. The mixture was quenched with 50%> ΝaHCO3 and extracted with ethyl acetate. The organic layer was separated and dried over MgSO4, filtered, and the solvents were evaporated. The residue was purified by HPLC reverse phase chromatography using water (0.1%> trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%>) to give 7 mg (45%o) ofthe title compound.
Example 593 methyl (4-{[3-((lS)-l-{[((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)amino]carbonyl} -2-methylpropyl)-2-oxo- 1 - imidazolidinyl]methyl}-l,3-thiazol-2-yl)methylcarbamate Example 587E (16.7 mg, 0.023 mmol) was dissolved in dichloromethane (0.4 mL) was treated with triethylamine (6.6 μL, 2 equivalents) and methyl chloroformate (2 μL, 1.1 equivalents) at 0 °C for 30 min. The solvents were evaporated and the residue was purified by HPLC reverse phase chromatography using water (0.1 % trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 12 mg (67%) ofthe title compound.
Example 594
(2S)-N-(( 1 S,2R)~ 1 -benzyl-2-hydroxy-3 - {isobutyl[(4-methoxyphenyl)sulfonyl] amino } propy 1)- 3-methyl-2-[3-({2-[(methylsulfonyl)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l- imidazolidinyl]butanamide
Example 594A tert-butyl (2S)-3-methyl-2-[3-({2-[(methylsulfanyl)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo- 1 -imidazolidinyl]butanoate Example 587B (28 mg, 0.062 mmol) was dissolved in N,N-dimethylforaιamide (0.6 mL) and treated with sodium methylthiolate (4.8 mg, 1.1 equivalents) at 25 °C for 16 h. The mixture was partitioned between saturated NH4C1 and ethyl acetate. The organic layer was separated and dried over MgSO4, filtered, and the solvents were evaporated. The residue was purified using ethyl acetate: dichloromethane (1:1) to give 17.4 mg (70%) ofthe title compound.
Example 594B (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 3-methyl-2-[3-({2-[(methylsulfanyl)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l- imidazolidinyl]butanamide Example 594A (57 mg, 0.142 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) and stined at 25 °C for 1 h. The solvents were evaporated and the crude acid used directly for the next step. The acid was dissolved in Ν,Ν-dimethylformamide (1 mL) and treated with EDAC (33 mg, 1.5 equivalents), HOBT (29 mg, 1.5 equivalents), N- methylmorpholine (0.16 mL, 1 equivalent) followed by the Example 18 (58 mg, 1 equivalent) and the mixture was stined at 25 °C for 16 h. The solvents were evaporated and the residue was purified using dichloromethane: ethyl acetate (1:1) to give 12 mg (11%) ofthe title compound.
Example 594C (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 3-methyl-2-[3-({2-[(methylsulfonyl)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l- imidazolidinyljbutanamide Example 594B (13 mg, 0.017 mmol) was dissolved in dichloromethane (0.4 mL) and treated with m-chloroperbenzoic acid (8.7 mg, 2 equivalents) at 25 °C for 30 min. The solvents were evaporated and the residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 11.2 mg (82%) ofthe title compound.
Example 595 (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 2-[3-({2-[(diethylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]-3- methylbutanamide Example 587E was treated in a similar manner as for Example 590 using acetaldehyde instead of formaldehyde was to prepare the title compound.
Example 596 (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 2-{3-[2-(isopropylamino)-2-oxoethyl]-2-oxo-l-imidazolidinyl}-3-methylbutanamide Example 620B (5.8 mg, 0.008 mmol) was dissolved in ethanol (0.3 mL) and treated with NaBH (5 mg) and the mixture was stined at 25 °C for 16 h. The solvents were evaporated and the residue was directly used for the next step. The imidazolone was dissolved in HO Ac (1 mL) and treated with Pd(OH)2 and a hydrogen balloon. The mixture was stined for 16 h, filtered, and the solvents were evaporated. The residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%>) to give 2.7 mg (46%. from imide) ofthe title compound.
Example 597 (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 3-methyl-2-[3-({2-[(methylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l- imidazolidinyl]butanamide
Example 597 A tert-butyl (2S)-3-methyl-2-[3-({2-[(methylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l- imidazolidinyl]butanoate Example 273D (200 mg, 0.54 mmol) was dissolved in toluene: ethanol (2.2 mL, 1:1) was added 2M methylamine in tetrahydrofuran (0.54 mL, 2 equivalents) was heated to 70 °C for 2 h. The mixture was cooled to 25 °C and NaBH4 (20 mg, 3 equivalents) was added and the mixture was stined at 25 °C for 16 h. The solvents were evaporated and the residue was partitioned between ethyl acetate and sat. NaHCO3, the organic layer was separated and washed with brine, dried over MgSO4, filtered, and evaporated. The residue was purified using chloroform: methanol (95:5) to give 118 mg (56%) ofthe title compound. Example 597B tert-butyl (2S)-2-{3-[(2-{[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]methyl}-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylbutanoate Example 597 A (118 mg, 0.3 mmol) was dissolved in dichloromethane (3 mL) a 0 °C and triethylamine (90 μL, 2.2 equivalents) followed by FMOC-C1 (86 mg, 1.1 equivalents). The mixture was stined at 25 °C for 16 h. The solvents were evaporated and the residue was purified using ethyl acetate: hexanes (1:1) to give 138 mg (76%>) of protected amine.
Example 597C 9H-fluoren-9-ylmethyl (4-{[3-((lS)-l-{[((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)amino] carbonyl} -2-methylpropyl)-2-oxo- 1 - imidazolidinyl]methyl} - 1 ,3 -thiazol-2-yl)methyl(methyl)carbamate Example 597B (60 mg, 0.099 mmol) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) and stined at 25 °C for 1 h. The solvents were evaporated and the acid was used directly for the next step. The crade acid was dissolved in N,N- dimethylformamide (1 mL) with HOBT (20 mg, 1.5 equivalents) EDAC (29 mg, 1.5 equivalents), and N-methylmorpholine (27 μL, 2.5 equivalents) followed by the Example 18 (40 mg, 1 equivalent). The mixture was stined at 25 °C for 16 h and the solvents were evaporated. The residue was purified using HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 40 mg (42%) ofthe title compound.
Example 597D
(2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 3-methyl-2-[3-( {2-[(methylamino)methyl]-l ,3-thiazol-4-yl}methyl)-2-oxo- 1 - imidazolidinyljbutanamide Example 597C (40 mg, 0.042 mmol) was dissolved in acetonitrile (0.5 mL) and diethylamine (10 μL, 3 equivalents), and the mixture was stined at 25 °C for 1 h. The solvents were evaporated and the residue was purified by HPLC reverse phase chromatography using water (0.1 %> trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%)) to give 13 mg (37%) ofthe title compound.
Example 598
(2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 2- [3 -( {2- [N-hydroxy ethanimidoyl] - 1 ,3 -thiazol-4-yl} methyl)-2-oxo- 1 -imidazolidinyl] -3 - methylbutanamide Example 540 was treated in a similar manner to Example 476G to give the title compound.
Example 599 (2S,3S)-2-(3-{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N- ((lS,2R)-l-benzyl-3-{(cyclopentylmethyl)[(4-methoxyphenyl)sulfonyl]amino}-2- hydroxypropyl)-3-methylpentanamide
Example 599A 9H-fluoren-9-ylmethyl (4-{[3-((lS,2S)-l-{[((lS,2R)-l-benzyl-3-{(cyclopentylmethyl)[(4- methoxyphenyl)sulfonyl]amino}-2-hydroxypropyl)amino]carbonyl}-2-methylbutyl)-2-oxo-l- imidazolidinyl]methyl} - 1 ,3-thiazol-2-yl)methylcarbamate Example 279F (15 mg, 0.027 mmol) was dissolved in N,N-dimethylformamide (0.3 mL) and treated with Example 522 (18 mg, 1.5 equivalents), EDAC (8 mg, 1.5 equivalents), HOBT (6 mg, 1.5 equivalents), and N-methylmorpholine (7 μL, 2.5 equivalents) at 25 °C for 16 h. The solvents were evaporated, and the residue was purified by HPLC reverse phase chromatography using water (0.1%> trifluoroacetic acid): acetonitrile (75:25) to acetonitrile (100%)) to give 12 mg (46%) ofthe title compound.
Example 599B (2S,3S)-2-(3-{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N- ((lS,2R)-l-benzyl-3-{(cyclopentylmethyl)[(4-methoxyphenyl)sulfonyl]amino}-2- hydroxypropyl)-3-methylpentanamide Example 599A (12 mg, 0.012 mmol) was dissolved in acetonitrile (0.2 mL) and treated with diethylamine (3 μL, 3 equivalents) at 25 °C for 2 h. The solvents were evaporated, and the residue was purified by HPLC reverse phase chromatography using water (0.1%) trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 10.6 mg (100%>) ofthe title compound.
Example 600 (2S,3S)-2-(3-{3-[amino(hydroxyimino)methyl]benzyl}-2-oxo-l-imidazolidinyl)-N-((lS,2R)- 1 -benzyl-2-hydroxy-3- {isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylpentanamide Example 570 (80 mg, 0.11 mmol) was dissolved in ethanol (1 mL) and treated with hydroxylamine hydrochloride (32 mg, 4 equivalents) and triethylamine (0.16 mL, 10 equivalents) at 50 °C for 9 h. The mixture was partitioned between water and ethyl acetate, the organic layer was separated, dried over Νa SO4, and the solvents were evaporated. The residue was purified using ethyl acetate to give 35 mg (42%>) ofthe title compound.
Example 601 (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 4-hydroxy-2- {3 - [( 1 -methyl- lH-benzimidazol-2-yl)methyl] -2-oxo- 1 - imidazolidinyl} butanamide
Example 601 A benzyl (lS)-l-{[((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)amino]carbonyl}-3-hydroxypropylcarbamate Example 521B (167 mg, 0.41 mmol) was dissolved in pyridine (0.4 mL) and treated with Z-aminobutyrolactone (193 mg, 2 equivalents) (CAS#35677-89-5) and heated to 100 °C for 2 d. The solvents were evaporated and the residue was purified using ethyl acetate to give 235 mg (66%) ofthe title compound.
Example 60 IB (26)-2-amino-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-4-hydroxybutanamide Example 601 A (73 mg, 0.11 mmol) was dissolved in methanol (2 L) and treated with Pd(OH)2/C and stined with a hydrogen balloon at 25 °C for 3 h. The mixture was filtered, rinsed with methanol, and the solvents were evaporated. The amine was used directly without purification.
Example 60 IC 9H-fluoren-9-ylmethyl 2-[((lS)-l-{[((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)amino]carbonyl}-3-hydroxypropyl)amino]ethyl[(l- methyl- lH-benzimidazol-2-yl)methyl]carbamate Example 601B (58 mg, 0.11 mmol) and Example 148C (49 mg, 1 equivalent) were dissolved in methanol (0.5 mL) and HO Ac (5 μL) and treated with ΝaCΝBH3 (15.4 mg, 2 equivalents) at 25 °C for 2 h. The mixture was partitioned between water and ethyl acetate, the organic layer was separated and washed with 10%> NaHCO3, brine and the solvents were evaporated. The residue was purified using 9% methanol/dichloromethane to give 81 mg (78%) ofthe title compound.
Example 60 ID (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyplιenyl)sulfonyl]amino}propyl)- 4-hydroxy-2- {3-[(l -methyl- lH-benzimidazol-2-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide Example 601C (81 mg, 0.088 mmol) was dissolved in Ν,Ν-dimethylformamide (0.9 mL) and treated with diethylamine (90 μL) at 25 °C for 1 h. The solvents were evaporated and the residue was dissolved in dichloroethane (1.8 mL) and treated with bis(p-nitrophenyl) carbonate (34 mg, 1.1 equivalents) and heated to 50 °C for 16 h. The mixture was partitioned with ethyl acetate and IN Na2CO3 and stined for 1 h, and the organic layer was separated. This layer was washed several times with IN Na CO3, separated, and the solvents were evaporated. The residue was purified using 9%> methanol/dichloromethane to give 46 mg (72%) the title compound.
Example 602 (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide Method C Example 292 (50 mg ) was combined with Ν-hydroxysuccinimide (28 mg, 1.1 equivalents) and DCC (49 mg, 1.1 equivalents) in dichloromethane (1 mL) and stined for 1 h at 25° C. The solids are filtered, and to this mixture was added Ν-methylmorpholine (35 μL, 1 equivalent) and Example 52 IB (72 mg, 1 equivalent). The mixture was stined for 16 h, evaporated, and was purified using 1% methanol/chloroform to give 74 mg (65%) ofthe title compound. Η ΝMR (300 MHz, CDC13) δ ppm 0.80 (dd, J=8.99, 6.61 Hz, 6 H), 0.87 (d, J=6.44 Hz, 3 H), 0.93 (m, 3 H), 1.82 (m, 1 H), 2.08 (m, 1 H), 2.30 (m, 1 H), 2.78 (m, 2 H), 3.01 (m, 2 H), 3.07 (m, 2 H), 3.23 (m, 1 H), 3.58 (d, J=17.97 Hz, 1 H), 3.81 (m, 3 H), 3.88 (s, 3 H), 3.94 (m, 1 H), 4.23 (m, 1 H), 4.73 (d, J=6.10 Hz, 2 H), 4.81 (s, 1 H), 4.86 (d, J=10.17 Hz, 1 H), 6.21 (d, J=9.49 Hz, 1 H), 6.99 (m, 2 H), 7.11 (m, 6 H), 7.72 (m, 2 H), 8.02 (s, 1 H). The compounds listed in Table 14, wherein X11; X7; and X3 represent respectively the points of connection to the core structure (K), were prepared by coupling the conesponding acids (Examples 291-360) with the conesponding amines (Examples 521-523) as exemplified in .
Figure imgf000223_0001
Table 14
Figure imgf000223_0002
Figure imgf000224_0001
Figure imgf000225_0001
Example 620
(2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 2-{3-[2-(isopropylamino)-2-oxoethyl]-2,4-dioxo-l-imidazolidinyl}-3-methylbutanamide
Example 620A [3-((lS)-l-{[((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)amino]carbonyl}-2-methylpropyl)-2,5-dioxo-l- imidazolidinyl] acetic acid Example 607 (161 mg, 0.24 mmol) was dissolved in tetrahydrofuran: water (0.9 mL, 3 : 1) and treated with LiOH (11 mg, 1.1 equivalents) at 25 °C for 2 h. The mixture was quenched with trifluoroacetic acid (20 μL), the solvents were evaporated and the residue was purified using 10% methanol (2% HOAc)/ethyl acetate to give 0.125 g (81%) ofthe acid. Example 620B
(2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)- 2-{3-[2-(isopropylamino)-2-oxoethyl]-2,4-dioxo-l-imidazolidinyl}-3-methylbutanamide Example 620A (24 mg, 0.037 mmol) was dissolved in Ν,Ν-dimethylformamide (0.4 mL) and treated with EDAC (10 mg, 1.5 equivalents), HOBT (7.5 mg, 1.5 equivalents), followed by isopropylamine (5 μL, 1 equivalent) and the mixture was stined at 25 °C for 16 h. The solvents were evaporated, and the residue was purified using acetonitrile to give 12 mg (47%>) ofthe title compound. The compounds listed in Table 15, wherein X0 represents the point of connection to the core structure (L), were prepared using the procedures as exemplified in Example 620A and Example 620B.
Figure imgf000226_0001
Table 15
Figure imgf000226_0002
Example 625 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-hydroxy-N-isobutylbenzenesulfonamide
Example 625A N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-(benzyloxy)-N-isobutylbenzenesulfonamide Example 1 (0.13 g, 0.39 mmol) was dissolved in dichloromethane (4 mL) and treated with triethylamine (0.12 mL, 2.2 equivalents) and j-benzyloxybenzenesulfonyl chloride (0.12 g, 1.1 equivalents) at 25 °C for 18 h. The crade mixture was purified using chloroform to give 0.22 g (97%) ofthe title compound.
Example 625B N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-hydroxy-N-isobutylbenzenesulfonamide Example 625 A (0.22 g, 0.38 mmol) was dissolved in ethyl acetate (4 mL) and treated with Pd(OH)2/C (0.1 g) and a hydrogen balloon at 25 °C for 2 h. The crude mixture was filtered, and the solvents were evaporated to give 0.2 g crude solid. This material was dissolved in dichloromethane: trifluoroacetic acid (6 mL, 1:1) at 25 °C for 1 h. The solvents was evaporated, the crade residue was azeotroped twice with toluene to give 0.205 g (100%>) crade amine as the trifluoroacetic acid salt. Example 626 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide
Example 626A tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- nitrophenyl)sulfonyl]amino}propylcarbamate Example 1 (0.64 g, 1.9 mmol) was dissolved in dichloromethane (20 mL) and treated with triethylamine (0.8 mL, 3 equivalents) and^-nitrobenzenesulfonyl chloride (0.46g, 1.1 equivalents) at 25 °C and stined for 4 h. The reaction mixture was evaporated and purified using 7% ethyl acetate/dichloromethane to give 0.88 g (89%) ofthe title compound.
Example 626B 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide Example 626A (0.88g, 1.7 mmol) was dissolved in ethyl acetate (17 mL) and treated with 20% Pd(OH)2/C (230 mg, 0.2 equivalent) and a hydrogen balloon at 25 °C for 1 h. The crude mixture was filtered and the solvents were removed by evaporation. This material was dissolved in dichloromethane: trifluoroacetic acid (10 mL, 1:1) at 25 °C for 1 h. The solvents were evaporated, the crade residue was azeotroped twice with ethyl acetate to give 0.75 g (100%) of crade product as the trifluoroacetic acid salt.
Example 627 3-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-chloro-N- isobutylbenzenesulfonamide Example 627A tert-butyl (lS,2R)-l-benzyl-3-[[(4-chloro-3-nitrophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropylcarbamate Example 1 (0.64 g, 1.9 mmol) was dissolved in dichloromethane (20 mL) and treated with triethylamine (0.8 mL, 3 equivalents) and ^-chloro-o-nitrobenzenesulfonyl chloride (0.54g, 1.1 equivalent) at 25 °C and stined for 4 h. The reaction mixture was evaporated and purified using 5% ethyl acetate/dichloromethane to give 0.88 g (85%) ofthe title compound.
Example 627B 3-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-chloro-N- isobutylbenzenesulfonamide Example 627A (0.85g, 1.53 mmol) was dissolved in ethanol: acetic acid (20 mL 1:1) and treated with iron (330 mg, 4 equivalents). The reaction was heated to 70 °C for 1 h. The reaction was evaporated and extracted twice with ethyl acetate. The organic layer was washed twice with saturated NaHCO3, dried over MgSO4, filtered, and evaporated to give 0.91 g of crude product. This material was treated with dichloromethane: trifluoroacetic acid (20 mL, 1:1) at 25 °C for 1 h. The solvents were evaporated to yield 0.80 g of Example 627B (100%).
Example 628 3-amino-N-[(2R,3iS)-3-amino-2-hydroxy-4-phenylbutyl]-4-hydroxy-N- isobutylbenzenesulfonamide
Example 628A 4-(benzyloxy)-3-nitrobenzenesulfonyl chloride To 10 g (41.5 mmol) of 4-hydroxy-3-nitro-benzenesulfonic acid sodium salt dissolved in ethanol (250 mL) was added benzyl bromide (5.4 mL, 1.1 equivalents), 15%) ΝaOH solution (13.2 mL, 1.2 equivalents), and water (40 mL). The mixture was heated to 70 °C for 5 h. Additional benzyl bromide (5.4 mL) and 15% ΝaOH solution (13 mL) was added and heating was continued for an additional 18 h. The ethanol was removed by evaporation. The reaction was filtered through a pad of Celite, washed with water, and dried in a vacuum oven at 50 °C to give 7 g of material. A portion of this material (1.5g, 4.56 mmol) was combined with phosphorous pentachloride (1.14 g, 1.2 equivalents) and phosphorous oxychloride (1.4 mL, 3.3 equivalents) and heated to 100 °C for 18 h. The reaction mixture was partitioned between chloroform and water. The organic layer was washed with a brine solution, dried over MgSO4, filtered, and evaporated to leave 1.4 g of crade title compound which was used in the subsequent step.
Example 628B tert-butyl ( 1 S,2R)- 1 -benzyl-3 - [ { [4-(benzyloxy)-3 -nitrophenyl] sulfonyl} (isobutyl)amino] -2- hydroxypropylcarbamate Example 1 (1.5 g, 4.4 mmol) was dissolved in 25 mL of dichloromethane and treated with Example 628A (1.4 g, 4.2 mmol) and triethylamine (1.3 mL, 2.2 equivalents). The reaction was stined at 25°C for 3 h. The crude mixture was purified using chloroform to give 1.83 mg (74%>) ofthe title compound.
Example 628C 3-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-hyαLxOxy-N- isobutylbenzenesulfonamide Example 628B (450mg, 0.72 mmol) was dissolved in ethyl acetate (60 mL) and treated with 20% Pd(OH)2/C (200 mg, 0.1 equivalent ) and a hydrogen filled balloon at 25 °C for 3 h. The reaction was filtered and evaporated to leave 376 mg of crade material. This was dissolved in dichloromethane: trifluoroacetic acid (6 mL, 1:1) and stined at 25 °C for 1.5 h. The solvents were removed by evaporation and the product was azeotroped with toluene (3x). The material was dissolved in ethyl acetate, washed with saturated NaHCO3 solution, washed with brine, dried over MgSO4, filtered, and evaporated to leave 328 mg (100%) ofthe title compound. Example 629 N-(5-{[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl}-2- hydroxyphenyl)- 1 -methyl- lH-imidazole-4-sulfonamide
Example 629A (lR,2S)-l-{[{[4-(benzyloxy)-3-nitrophenyl]sulfonyl}(isobutyl)amino]methyl}-2-[(tert- butoxycarbonyl)amino]-3-phenylpropyl acetate Example 628B (1.83 g, 2.9 mmol) was dissolved in dichloromethane (30 mL) and treated with triethylamine (0.6 mL, 1.5 equivalents), acetic anhydride (0.3 mmol, 1.1 equivalents), and a catalytic amount of 4-(dimethylamino)pyridine. The reaction was stined at 25 °C for 18h and purifie using ethyl acetate/hexane to yield 1.82 g (93%>) ofthe title compound.
Example 629B (lR,2S)-l-{[{[3-amino-4-(benzyloxy)phenyl]sulfonyl}(isobutyl)amino]methyl}-2-[(tert- butoxycarbonyl)amino]-3-phenylpropyl acetate Example 629A (1.8 g, 2.7 mmol) was dissolved ethanol (25 mL) and acetic acid (5 mL). The solution was treated with iron powder (600 mg, 4equivalents) and heated to 50 °C for 1.5 h. The solvents were removed by evaporation. The reaction was dissolved in chloroform and washed with a saturated solution of ΝaHCO3, washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified using chloroform and ethyl acetate to give 651 mg (38%) ofthe title compound.
Example 629C (lR,2S)-l-{[[(4-(benzyloxy)-3-{[(l-methyl-lH-imidazol-4- yl)sulfonyl]amino}phenyl)sulfonyl](isobutyl)amino]methyl}-2-[(tert- butoxycarbonyl)amino]-3-phenylpropyl acetate Example 629B (75 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane and treated with triethylamine (0.049 mL, 3 equivalents), l-methylimidazole-4-sulfonyl chloride (32 mg, 1.5 equivalents), and a catalytic amount of 4-(dimethylamino)pyridine. The reaction was stined at 40°C for 4 h. The reaction was purified using 2%>methanol/CHCl3 to give 36 mg (39%o) ofthe title compound.
Example 629D tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3-{[(l-methyl-lH-imidazol-4- yl)sulfonyl]amino}phenyl)sulfonyl](isobutyl)amino]propylcarbamate Example 629C (24 mg, 0.031 mmol) was dissolved in 1 mL of methanol and treated with 20%) Pd(OH)2/C (20 mg) and stined at 25 °C under a hydrogen balloon atmosphere for 1 h. The reaction was filtered and evaporated to give 19 mg of crude product. This material (19 mg, 0.027 mmol) was dissolved in 0.5 mL of methanol and treated with K2CO3 (4.2 mg, 1.1 equivalents) and stined at 25 °C for 3 h. The reaction was evaporated and purified using 7%methanol/CHCl3 to give 5.1 mg ofthe title compound (26%.).
Example 629E N-(5-{[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl}-2- hydroxyphenyl)- 1 -methyl- lZ -imidazole-4-sulfonamide Example 629D (5 mg, 0.008 mmol) was dissolved in dichloromethane: trifluoroacetic acid (0.5 mL, 2:1) and stined at 25 °C for 1 h. The reaction was evaporated and azeotroped with toluene (3x) to give the title compound.
Example 630 N-(5-{[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl}-2- hydroxyphenyl)-3-pyridinesulfonamide
Example 630A 3-pyridinesulfonyl chloride A mixture of 3-pyridinesulfonic acid (1.0 g, 6.3 mmol), phosphorous pentachloride
(1.6 g, 1.2 mmol), and phosphorous oxychloride (2.0 mL, 3.3 mmol) was combined and stined at 100 °C for 18 h. The reaction was cooled to 25 °C, diluted with CHC13, and bubbled with HCI gas. The resulting precipitate was collected by filtration, washed with CHC13, and dried in vacuo to yield 1.12 g ofthe title compound (84%>). Example 63 OB (lR,2S)-l-{[({4-(benzyloxy)-3-[(3- pyridinylsulfonyl)amino]phenyl}sulfonyl)(isobutyl)amino]methyl}-2-[(tert- butoxycarbonyl)amino]-3-phenylpropyl acetate Example 629B (75 mg, 0.12 mmol) was dissolved in 1.2 mL of dichloromethane and treated with pyridine (0.033 mL, 3.5 equivalents) and Example 630A (43 mg, 1.7 equivalents) at 25 °C and stined for 72 h. The reaction was evaporated and purified using 25% ethyl acetate/chloroform to yield 67 mg ofthe title compound (72%). Example 630C tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-[( {4-hydroxy-3-[(3- pyridinylsulfonyl)amino]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate Example 630B (67 mg, 0.086 mmol) was dissolved in 1 mL of methanol and treated with K2CO3 (15 mg, 1.2 equivalents) at 25 °C for 18 h. The reaction was diluted with chloroform and washed with a saturated solution of NH4C1, which was back extracted with chloroform. The organics were combined and washed with brine, dried over MgSO4, filtered, and evaporated to yield 66 mg of crade product. This material was dissolved in 1 mL of methanol and treated with 20% Pd(OH)2/C (30 mg, 0.5 mmol) and stined at 25 °C under hydrogen balloon pressure for 2 h. The reaction was filtered, evaporated, and purified using 5% methanol/CHCl3 to give 22.8 mg (40%) ofthe title compound.
Example 630D N-(5-{[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl}-2- hydroxyphenyl)-3-pyridinesulfonamide Example 630C (22 mg, 0.034 mmol) was dissolved in dichloromethane: trifluoroacetic acid (0.4 mL, 1:1) and stined at 25 °C for 1.5 h. The reaction was evaporated and azeotroped with toluene (3x) to give the title compound.
Example 631 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-hydroxy-N-isobutyl-3- [(methylsulfonyl)amino]benzenesulfonamide
Example 631 A (lR,2S)-l-{[({4-(benzyloxy)-3- [(methylsulfonyl)amino]phenyl} sulfonyl)(isobutyl)amino]methyl} -2-[(tert- butoxycarbonyl)amino]-3-phenylpropyl acetate Example 628B (75 mg, 0.11 mmol) was dissolved in 1.1 mL of dichloromethane, cooled to -78 °C and treated with pyridine (0.027 mL, 3 equivalents), and methanesulfonyl chloride (0.016 mL, 1.8 equivalents). The reaction was allowed to warm to 25 °C and stined for 18 h. The reaction mixture was evaporated and purified using 20%> ethyl acetate/chloroform to give 91 mg ofthe title compound (99%>).
Example 63 IB tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-hydroxy-3- [(methylsulfonyl)amino]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate Example 631A (90 mg, 0.13 mmol) was dissolved in 1.3 mL of methanol, treated with
K2CO3 (21 mg, 1.2 equivalents), and stined at 25 °C for 1.5 h. The reaction was diluted with chloroform and washed with a saturated solution of NH4C1, which was back extracted with CHC13. The organics were combined and washed with brine, dried over MgSO4, filtered, and evaporated to yield 83 mg of crade product. This material was dissolved in 1.2 mL of methanol and treated with 20%> Pd(OH) /C (40 mg) and stined at 25 °C under hydrogen balloon pressure for 2 h. The reaction was filtered, evaporated, and purified using 5%> methanol/CHCl3 to give 38 mg (52%>) ofthe title compound.
Example 63 IC N-[(2R,3S)-3-amino-2-hydroxy-4-ρhenylbutyl]-4-hydroxy-N-isobutyl-3- [(methylsulfonyl)amino]benzenesulfonamide Example 63 IB (35 mg, 0.060 mmol) was dissolved in dichloromethane: trifluoroacetic acid (0.3 mL, 1:1) and stined at 25 °C for 1.5 h. The reaction was evaporated and azeotroped with toluene (3x) to give the title compound.
Example 632 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3,5-dichloro-4-hydroxy-N- isobutylbenzenesulfonamide 3,5-dichloro-4-hydroxy benzenesulphonyl chloride (97 mg, 0.372 mmol) was dissolved in 1 mL of dichloromethane and treated with NO-bis(trimethylsilyl)acetamide
(0.092 mL, 1 equivalent) and stined at 25 °C for 5 h. The reaction mixture was treated with Example 1 (100 mg, 0.8 equivalents) and triethylamine (0.109 mL, 2.1 equivalents) and stined an additional hour. The reaction was diluted with dichloromethane washed with water, dried over MgSO4, filtered, and evaporated to give 240 mg of a foamy solid. This material was stined with dichloromethane: trifluoroacetic acid (4.5 mL, 2:1) for 1.5 h. The reaction was evaporated, redissolved in 10%>methanol/dichloromethane, washed with saturated NaHCO3 solution, and purified using 10%> methanol/dichloromethane to give 80 mg ofthe title compound (58%ι).
Example 633 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3,5-dichloro-2-hydroxy-N- isobutylbenzenesulfonamide 3,5-dichloro-6-hydroxy benzenesulphonyl chloride (97 mg, 0.372 mmol) was dissolved in 1 mL of dichloromethane and treated with NO-bis(trimethylsilyl)acetamide (0.092 mL, 1 equivalent) and stined at 25 °C for 5 h. The reaction mixture was treated with Example 1 (100 mg, 0.8 equivalents) and triethylamine (0.109 mL, 2.1 equivalents) and stined an additional hour. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, and evaporated to give 240 mg of a foamy solid. This material was stined with dichloromethane: trifluoroacetic acid (4.5 mL, 2:1) for 1.5 h. The reaction was evaporated, redissolved in 10%)inethanol/dichloromethane, washed with saturated ΝaHCO3 solution, and purified using 10%methanol/dichloromethane to give 79 mg ofthe title compound (57%>).
Example 634 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-hydroxy-N-isobutyl-3- methylbenzenesulfonamide
Example 634A 4-(benzyloxy)-3-methylbenzenesulfonyl chloride O-Cresol-4-sulfonic acid (6 g, 31.88 mmol) was stined with benzyl bromide (9.5 mL, 2.5 equivalent), 15%> aqueous ΝaOH (34 mL, 4 equivalents), and ethanol (150 mL) at 67 °C for 22h. The solvent was evaporated and the reaction was slurried with 10 mL of water, filtered, and the resulting white solid was washed with water twice. The material was dried in vacuo to give 8.2 g ofthe O-benzylated sodium salt. A portion of this material (4.0g, 15.1 mmol) was stined with phosphorous pentachloride (4.4 g, 1.5 equivalents) for 10 minutes. The mixture was partitioned between dichloromethane and water. The organic layer was separated, dried over MgSO4, filtered and the solvent was removed by evaporation to give 3.29 g (77%) ofthe title compound. Example 634B tert-butyl (lS,2R)-l-benzyl-3-[{[4-(benzyloxy)-3-methylphenyl]sulfonyl}(isobutyl)amino]-2- hydroxypropylcarbamate Example 1 (100 mg, 0.30 mmol) dissolved in 2 mL of dichloromethane was combined with Example 634A (lmg, 1.2 equivalents) and triethylamine (.0125 mL, 3 equivalents) and stined for 4 h. The reaction was purified using l%methanol/dichloromethane to give 200 mg (100%)) of crade title compound.
Example 634C N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-hydroxy-N-isobutyl-3- methylbenzenesulfonamide Example 634B (200 mg crade, 0.3 mmol) was dissolved in 2 mL of ethanol and treated with 10% Pd/C (100 mg). The reaction was stined under hydrogen balloon pressure for 24 h. The reaction was filtered, evaporated, and purified using l%>methanol/dichloromethane to give 80 mg ofthe debenzylated product. This material was stined with dichloromethane: trifluoroacetic acid (3 mL, 2:1) for 2.5 h. The solvents were evaporated, and the product was dissolved in dichloromethane, washed with ΝaHCO3, dried over MgSO4, filtered and concentrated to yield 70 mg (57%>) ofthe title compound. Example 635 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-5-fluoro-4-hydroxy-N-isobutyl-2- methylbenzenesulfonamide
Example 635A 5-fluoro-4-hydroxy-2-methylbenzenesulfonyl chloride To a solution of chlorosulfonic acid (1.5 g, 13.3 mmol) dissolved in 10 mL of dichloromethane was added 2-fluoro-5-methylphenol (1.1 g, 8.86 mmol) dropwise. After 10 minutes, the reaction was quenched by adding to ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO4, filtered, and concentrated to give 150 mg (7.5%o) ofthe title compound.
Example 635B N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-5-fluoro-4-hydroxy-N-isobutyl-2- methylbenzenesulfonamide Example 635A (95 mg, 0.424 mmol) was dissolved in 1 mL of dichloromethane, treated withNO-bis(trimethylsilyl)acetamide (0.105 mL, 1 equivalent), and stined at 25 °C for 5 h. The reaction mixture was treated with Example 1 (100 mg, 0.7 equivalent), triethylamine (0.109 mL, 2.1 equivalents), and stined an additional hour. The reaction was diluted with dichloromethane washed with water, dried over MgSO4, filtered, and evaporated give a foamy solid. This material was stined with dichloromethane: trifluoroacetic acid (4.5 mL, 2:1) for 1.5 h. The reaction was evaporated, redissolved in 10%> methanol/dichloromethane, washed with saturated NaHCO3 solution, and purified using 10%)methanol/dichloromethane to give 53 mg ofthe title compound (42%>).
Example 636 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-5-chloro-4-hydroxy-N-isobutyl-2- methylbenzenesulfonamide
Example 636A 5-chloro-4-hydroxy-2-methylbenzenesulfonyl chloride To a solution of chlorosulfonic acid (1.22 g, 10.5 mmol) dissolved in 10 mL of dichloromethane was added 2-chloro-5-methylphenol (1.0 g, 7.0 mmol) dropwise. After 10 minutes, the reaction was quenched by pouring it into ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO4, filtered, and concentrated to give 120 mg (7.1 %>) of the title compound. f Example 636B N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-5-chloro-4-hydroxy-N-isobutyl-2- methylbenzenesulfonamide Example 636A (120 mg, 0.50 mmol) was dissolved in 1 mL of dichloromethane, treated with NO-bis(trimethylsilyl)acetamide (0.123 mL, 1 equivalent), and stined at 25 °C for 5 h. The reaction mixture was treated with Example 1 (117 mg, 0.7 equivalent), triethylamine (0.106 mL, 2.1 equivalents), and stined an additional hour. The reaction was diluted with dichloromethane, washed with water, dried over MgSO , filtered, and evaporated to give a foamy solid. This material was stined with dichloromethane: trifluoroacetic acid (4.5 mL, 2:1) for 1.5 h. The reaction was evaporated, redissolved in 10%methanol/dichloromethane, washed with saturated ΝaHCO3 solution, and purified using 10%methanol/dichloromethane to give 33 mg (21%) ofthe title compound.
Example 637 N-[(2R,36)-3-amino-2-hydroxy-4-phenylbutyl]-3-chloro-4-hydroxy-N-isobutyl-5- methylbenzenesulfonamide
Example 637A 3-chloro-4-hydroxy-5-methylbenzenesulfonyl chloride To a solution of chlorosulfonic acid (1.22 g, 10.5 mmol) dissolved in 10 mL of dichloromethane was added 2-chloro-5-methylphenol (1.0 g, 7.0 mmol) dropwise. After 10 minutes, the reaction was quenched by pouring it into ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO4, filtered, and concentrated to give 190 mg (11.3%) ofthe title compound.
Example 637B N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-chloro-4-hydroxy-N-isobutyl-5- methylbenzenesulfonamide Example 637A (190 mg, 0.788 mmol) was dissolved in 2 mL of dichloromethane, treated withNO-bis(trimethylsilyl)acetamide (0.194 mL, 1 equivalent), and stined at 25 °C for 5 h.t The reaction mixture was treated with Example 1 (183 mg, 0.7 equivalent), triethylamine (0.230 mL, 2.1 equivalents), and stined an additional hour. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4; and evaporated to give a foamy solid. This material was stined with dichloromethane: trifluoroacetic acid (4.5 mL, 2:1) for 2 h. The reaction was evaporated, redissolved in 10%methanol/dichloromethane, washed with saturated ΝaHCO3 solution, and purified using 7% methanol/dichloromethane to give 110 mg (46%>) ofthe title compound. Example 638 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-chloro-4-hydroxy-N-isobutyl-5- methylbenzenesulfonamide Example 638 A 2-chloro-4-hydroxy-5-methylbenzenesulfonyl chloride To a solution of chlorosulfonic acid (3.69 g, 31.65 mmol) dissolved in 30 mL of dichloromethane was added 3-chloro-6-methylphenol (3.0 g, 21.1 mmol) dropwise. After 10 minutes, the reaction was quenched by pouring it into ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO4, filtered, and concentrated to give 120 mg (2.4%) ofthe title compound.
Example 638B N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-chloro-4-hydroxy-N-isobutyl-5- methylbenzenesulfonamide Example 638A (120 mg, 0.497 mmol) was dissolved in 2 mL of dichloromethane, treated with NO-bis(trimethylsilyl)acetamide (0.135 mL, 1.1 equivalents), and stined at 25 °C for 5 h. The reaction mixture was treated with Example 1 (132 mg, 0.7 equivalent), triethylamine (0.164 mL, 2.1 equivalents), and stined an additional hour. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, filtered, and evaporated to give a foamy solid. This material was stined with dichloromethane: trifluoroacetic acid (4.5 mL, 2: 1) for 2 h. The reaction was evaporated, redissolved in
10%methanol/dichloromethane, washed with saturated NaHCO3 solution, and purified using 7% methanol/dichloromethane to give 25 mg (14.5%) ofthe title compound.
Example 639 N-[(2R,3»S)-3-amino-2-hydroxy-4-phenylbutyl]-4-hydroxy-N-isobutyl-3- {[(methylamino)sulfonyl]amino}benzenesulfonamide
Example 639 A 4-hydroxy-3 -nitrob enzenesulfonyl chloride To a solution of chlorosulfonic acid (12.0 mL, 180 mmol) at 0 °C was added 2- nitrophenol (8.35g, 60.0 mmol) in small portions over 1 h. The reaction was heated to 60 °C for 20 minutes and allowed to stir for 18 h at 25 C. The reaction was quenched by pouring it into 100 g of ice. The reaction was extracted with chloroform (3x), washed with cold water (2x), dried over MgSO4, filtered, and concentrated to give 9.06 g (64%>) ofthe title compound.
Example 639B tert-butyl ( 1S,2R)- 1 -benzyl-2-hydroxy-3 - [[(4-hydroxy-3 - nitrophenyl)sulfonyl](isobutyl)amino]propylcarbamate Example 639A (1.06 g, 4.46 mmol) was dissolved in 22 mL of dichloromethane, treated with NO-bis(trimethylsilyl)acetamide (1.1 mL, 1 equivalent), and stined at 25 °C for 3 h. The reaction mixture was treated with Example 1 (1.5 g, 1 equivalent) in 10 mL of dichloromethane, triethylamine (2.0 mL, 3 equivalents), and stined over 72 h. The reaction was washed with water, dried over MgSO4, filtered, and evaporated. This material was dissolved in tetrahydrofuran (20 mL) and treated with tetrabutylammonium fluoride (15.0 mL, 3 equivalents) for 2 h. at 25 °C. Ethyl acetate was added and the reaction was washed with 10%) citric acid, water (2x), and brine. The reaction was dried over MgSO4, filtered and concentrated to give 2.1 g (87.5%) ofthe title compound.
Example 639C tert-butyl (lS,2R)-l-benzyl-3-{isobutyl[(3-nitro-4-{[2- (trimethylsilyl)ethoxy]methoxy}phenyl)sulfonyl]amino}-2-{[2- (trimethylsilyl)ethoxy]methoxy}propylcarbamate Example 639B (l.Og, 1.86 mmol) in 10 mL of NN-dimethylformamide was treated with 2-(trimethylsilyl)ethoxymethyl chloride (1.30 mL, 4.0 equivalents) and NN- diisopropylethylamine (2.0 mL, 6 equivalents) at 50 °C for 18 h. The reaction was diluted with ethyl acetate and washed with water (2x) followed by brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified using 5%> ethyl acetate/dichloromethane to give 870 mg (58%) ofthe title compound.
Example 639D tert-butyl (lS,2R)-3-[[(3-amino-4- {[2- (trimethylsilyl)ethoxy]methoxy}phenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-{[2- (trimethylsilyl)ethoxy]methoxy}propylcarbamate Example 639C (800 mg, 1.0 mmol) was dissolved in 5 mL of ethyl acetate and treated with 20% Pd(OH)2/C (200 mg, 0.28 equivalent) under hydrogen balloon pressure for 3 h. The reaction was filtered, concentrated and purified using 5%> ethyl acetate/chloroform to give 599 mg (78%) ofthe title compound.
Example 639E tert-butyl ( 1 S,2R)- 1 -benzyl-3 - {isobutyl[(3 - { [(methylamino)sulfonyl] amino } -4- { [2- (trimethylsilyl)ethoxy]methoxy } phenyl)sulfonyl] amino } -2- { [2- (trimethylsilyl)ethoxy]methoxy}propylcarbamate Example 639D (100 mg, 0.13 mmol) in 1.3 mL of dichloromethane was treated with pyridine (0.025 mL, 2.4 equivalents) and N-methyl sulfamoyl chloride (ref: JOC 1976, 41, 4028)(0.014 mL, 1.2 equivalent) at 25 °C for 18 h. The reaction was concentrated and purified using 10%> ethyl acetate/chloroform to give 106 mg (95%) ofthe title compound.
Example 639F' N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-hydroxy-N-isobutyl-3- { [(methylamino)sulfonyl] amino } benzenesulfonamide Example 639E (25 mg, 0.03 mmol) was dissolved in methanol (0.22 mL) and 4 Ν HCI (0.07 mL, 9.3 equivalents). The reaction was stined at 25 °C for 18 h. The reaction was concentrated to give 15 mg (100%) ofthe title compound.
Example 640 ethyl 5- {[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl} -2- hydroxyphenylcarbamate
Example 640A tert-butyl (lS,2R)-l-benzyl-3-[[(3-[(ethoxycarbonyl)amino]-4-{[2- (trimethylsilyl)ethoxy]methoxy}phenyl)sulfonyl](isobutyl)amino]-2-{[2- (trimethylsilyl)ethoxy]methoxy}propylcarbamate Example 639D (50 mg, 0.065 mmol) was dissolved in 0.7 mL of dichloromethane and treated with pyridine (0.012 mL, 2.4 equivalents) and ethyl chloroformate (0.007 mL, 1.2 equivalents). The reaction was stined at 25 °C for 18 h, and the crude mixture was purified using 10% ethyl acetate/chloroform to give 49.6 (90%) ofthe title compound.
Example 640B ethyl 5-{[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl}-2- hydroxyphenylcarbamate Example 640A (57 mg, 0.067 mmol) was dissolved in 0.75 mL of methanol, treated with 4 N HCI (0.25 mL, 15 equivalents) and stined at 25 °C for 2 h. The solvents were evaporated to yield 32 mg ofthe title compound (100%>).
Example 641 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-hydroxy-N-isobutyl-3- (methylamino)benzenesulfonamide Example 641A tert-butyl (lS,2R)-l-benzyl-3-{isobutyl[(3-(methylamino)-4-{[2- (trimethylsilyl)ethoxy]methoxy}phenyl)sulfonyl]amino}-2-{[2- (trimethylsilyl)ethoxy]methoxy}propylcarbamate Example 639D (125 mg, 0.16 mmol) was dissolved in 1.8 mL of acetonitrile and treated with formaldehyde (0.065 mL, 5 equivalents), sodium cyanoborohydride (20 mg, 2 equivalents), and acetic acid (0.018 mL, 2 equivalents). The reaction was stined for 18 h at 25 °C, and the crade mixture was purified using 10%) ethyl acetate/chloroform to give 39 mg (3 /o) ofthe title compound. Example 641B N-[(2R,3S)-3-amino-2-hydroxy-4-ρhenylbutyl]-4-hydroxy-N-isobutyl-3- (methylamino)benzenesulfonamide Example 641A (36 mg, 0.05 mmol) was dissolved in 0.3 mL of methanol and treated with 4 Ν HCI (0.3 mL, 24 equivalents). Stirring was continued at 25 °C for 2 h. The reaction was concentrated to yield 21 mg ofthe title compound (100%)).
Example 642 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-(dimethylamino)-4-hydroxy-N- isobutylbenzenesulfonamide
Example 642A tert-butyl (lS,2R)-l-benzyl-3-[[(3-(dimethylamino)-4-{[2- (trimethylsilyl)ethoxy]methoxy}phenyl)sulfonyl](isobutyl)amino]-2-{[2- (trimethylsilyl)ethoxy]methoxy}propylcarbamate Example 639D (125 mg, 0.16 mmol) was dissolved in 1.8 mL of acetonitrile and treated with formaldehyde (0.065 mL, 5 equivalents), sodium cyanoborohydride (20 mg, 2 equivalents), and acetic acid (0.018 mL, 2 equivalents). The reaction was stined for 18 h. at 25 °C. Purification was performed using 10%> ethyl acetate/chloroform to give 54 mg (43%) ofthe title compound.
Example 642B N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-(dimethylamino)-4-hydroxy-N- isobutylbenzenesulfonamide Example 642A (54 mg, 0.07 mmol) was dissolved in 0.4 mL of methanol and treated with 4 Ν HCI (0.4 mL, 23 equivalents). Stirring was continued at 25 °C for 2 h. The reaction was concentrated to yield 30 mg ofthe title compound (100%o).
Example 643 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-{[(ethylamino)carbonyl]amino}-4-hydroxy- N-isobutylbenzenesulfonamide Example 643A tert-butyl (lS,2R)-l-benzyl-3-[[(3-{[(ethylamino)carbonyl]amino}-4-{[2- (trimethylsilyl)ethoxy]methoxy}phenyl)sulfonyl](isobutyl)amino]-2-{[2- (trimethylsilyl)ethoxy]methoxy}propylcarbamate Example 639D (50 mg, 0.065 mmol) was dissolved in 0.2 mL of toluene and treated with ethyl isocyanate (0.1 mL, 20 equivalents). The reaction was stined at 50 °C for 18 h. Purification was performed using 10%> ethyl acetate/chloroform to give 35.3 (64%>) ofthe title compound.
Example 643B N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-{[(ethylamino)carbonyl]amino}-4-hydroxy- N-isobutylbenzenesulfonamide Example 643A (35 mg, 0.042 mmol) was dissolved in 0.25 mL of methanol and treated with 4 N HCI (0.25 mL, 24 equivalents). Stirring was continued at 25 °C for 2 h. The reaction was concentrated to yield 30 mg ofthe title compound (100%). , Example 644 methyl 5-{[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl}-2- hydroxyphenylcarbamate
Example 644A tert-butyl (lS,2R)-l-benzyl-3-{isobutyl[(3-[(methoxycarbonyl)amino]-4-{[2- (trimethylsilyl)ethoxy]methoxy } phenyl)sulfonyl] amino } -2- { [2- (trimethylsilyl)ethoxy]methoxy}propylcarbamate Example 639D (57 mg, 0.074 mmol) was dissolved in 0.8 mL of dichloromethane and treated with pyridine (0.014 mL, 2.4 equivalents) and methyl chloroformate (0.007 mL, 1.2 equivalents). The reaction was stined at 25 °C for 18 h. Purification was performed using 10% ethyl acetate/chloroform to give 58.0 (95%>) ofthe title compoimd.
Example 644B methyl 5-{[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl}-2- hydroxyphenylcarbamate Example 644A (56 mg, 0.068 mmol) was dissolved in 0.3 mL of methanol and treated with 4 N HCI (0.3 mL, 18 equivalents) and stined at 25 °C for 2 h. The reaction was concentrated to yield 31 mg ofthe title compound (100%>). Example 645 benzyl 5- {[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl} -2- hydroxyphenylcarbamate
Example 645A benzyl 5- {[((2R,3S)-3-[(tert-butoxycarbonyl)amino]-4-phenyl-2- {[2- (trimethylsilyl)ethoxy]methoxy }butyl)(isobutyl)amino] sulfonyl} -2- { [2- (trimethylsilyl)ethoxy]methoxy}phenylcarbamate Example 639D (57 mg, 0.074 mmol) was dissolved in 0.8 mL of dichloromethane and treated with pyridine (0.014 mL, 2.4 equivalents) and benzyl chloroformate (0.013 mL, 1.2 equivalents). The reaction was stined at 25 °C for 18 h. Purification was performed using 10% ethyl acetate/chloroform to give 51.4 (78%) ofthe title compound. Example 645B benzyl 5-{[[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl](isobutyl)amino]sulfonyl}-2- hydroxyphenylcarbamate Example 645A (49 mg, 0.056 mmol) was dissolved in 0.3 mL of methanol and treated with 4 N HCI (0.3 mL, 21 equivalents). Stirring was continued at 25 °C for 2 h. The reaction was concentrated to yield 30 mg (100%) ofthe title compound.
Example 646 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-hydroxy-N- isobutylbenzenesulfonamide hydrate
Example 646A 2-oxo-2,3-dihydro-l,3-benzoxazole-6-sulfonyl chloride Benzoxazolinone (13.5 g, 0.1 mol) was added slowly to a 0 °C solution of chlorosulfonic acid (33.29 mL, 5 equivalents). The reaction was warmed to 25 °C and stined for 0.5 h, heated to 60°C for 3 h. The reaction was cooled to 25 °C, poured into ice, filtered, and rinsed with water. The resulting white solid was redissolved in 500 mL of diethyl ether and washed with water (2x), dried over Νa2SO4, filtered and concentrated to 100 mL volume. Hexane was added (100 mL) and the white precipitate was filtered and placed under vacuum to yield 17 g (73%) ofthe title compound.
Example 646B tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(2-oxo-2,3-dihydro-l,3-benzoxazol-6- yl)sulfonyl]amino}propylcarbamate Example 1 (200 mg, 0.6 mmol) was dissolved in 4 mL of dichloromethane and treated with Example 646A (175 mg, 1.25 equivalents) and triethylamine (0.21 mL, 2.5 equivalents). Stirring was maintained for 16 h. at 25 °C. The reaction was purified using 2%methanol/dichloromethane to give 370 mg (58%>) ofthe title compound. Example 646C 4-amino-N-[(2R,3iS)-3-amino-2-hydroxy-4-phenylbutyl]-3-hydroxy-N- isobutylbenzenesulfonamide Example 646B (370 mg, 0.694 mmol) was dissolved in 0.5 mL of dichloromethane and treated with trifluoroacetic acid (1.7 mL). The reaction was stined for 3 h at 25 °C, quenched with 50 mL of water, and made alkaline to pH=9 with sodium bicarbonate. Extract with ethyl acetate, filter off the precipitate, dry the organic layer over Νa SO4, filter, and concentrate to give 290 mg ofthe intermediate. A portion of this material (120 mg, 0.23 mmol) was dissolved in 1 mL of methanol, treated with 3mL of 30%> NaOH solution, and heated to 80 °C for 3 h. The solvents were evaporated and the crude residue was extracted with ethyl acetate. The material was purified using 10%> methanol/dichloromethane (w/ 1%. NH4OH) to yield 67 mg (60%) ofthe title compound. Example 647 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-4-(2-hydroxyethyl)-N- isobutylbenzenesulfonamide
Example 647A tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- vinylphenyl)sulfonyl]amino}propylcarbamate Example 1 (2.27 g, 6.8 mmol) in 20 mL of dichloromethane at 25 °C was treated with triethylamine (3.75 mL, 4 equivalents) followed by dropwise addition of 4-vinylbenzene sulfonyl chloride (1.6 g, 1.2 equivalents). Stirring was continued for 16 h. after which the reaction was quenched with 1 Ν ΝaHCO3, and evaporated. The material was purified using 20%) ethyl acetate/hexane to give 1.5 g (44%) ofthe title compound.
Example 647B tert-butyl (lS,2R)-l-benzyl-2-hydroxy-3-[{[4-(2- hydroxyethyl)phenyl]sulfonyl} (isobutyl)amino]propylcarbamate Example 647A (100 mg, 0.2 mmol) was dissolved in 3 mL of tetrahydrofuran at 0 °C and treated with borane-methyl sulfide complex (2 M/tetrahydrofuran, 0.3 mL, 3 equivalents). Stirring was continued for 3 h after which water (0.8 mL), followed by an aqueous solution of 1 N NaOH (0.3 ml) was added. The reaction allowed to warm to 25 °C and 30%» H O2 (0.2 mL) was added. After stirring for 30 min., the reaction was partitioned between brine and ethyl acetate. The organic layer was concentrated and the material was purified using 40%> ethyl actetate/hexanes to give 45 mg (43.5%>) ofthe title compound.
Example 647C N-[(2R,3S)-3-amino-2-hydroxy-4-ρhenylbutyl]-4-(2-hydroxyethyl)-N- isobutylbenzenesulfonamide Example 647B (37 mg, 0.0712 mmol) was dissolved in 0.2 mL of dichloromethane and treated with 0.8 mL of trifluoroacetic acid and stined at 25 °C for 3 h. The reaction was evaporated and purified using 5%ι methanol/dichloromethane (w/ 0.5%o ΝH4OH) to give 16 mg (53.5%o) ofthe title compound.
Example 648 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4- [(methylsulfonyl)amino]benzenesulfonamide
Example 648A tert-butyl (1S,2R)- 1 -benzyl-2-hydroxy-3- {isobutyl[(4- nitrophenyl)sulfonyl] amino } propy lcarbamate Example 1 (400 mg, 1.2 mmol) was dissolved in 8 mL of dichloromethane and treated with /p-nitro benzenesulfonyl chloride (0.316 g, 1.2 equivalents) and triethylamine (0.414 mL, 2.5 equivalents). The reaction was stined at 25 °C for 16 h, and purified using 2% methanol/dichloromethane to give 0.56 g (90%>) ofthe title compound.
Example 648B tert-butyl (lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropylcarbamate Example 648A (0.56 g, 1.07 mmol) in 10 mL of ethyl acetate was treated with 20%
Pd(OH) /C (0.35 g, 0.2 equivalent) under a hydrogen balloon atmosphere for 2 h. The reaction was filtered, evaporated, and purified using 5% methanol/dichloromethane to give 520 mg (98%) ofthe title compound. Example 648C N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4- [(methylsulfonyl)amino]benzenesulfonamide Example 648B (150 mg, 0.3 mmol) in 0.5 mL of dichloromethane was treated with pyridine (0.5 mL, 20 equivalents) and methanesulfonyl chloride (0.06 mL, 2.2 equivalents) at 25 °C for 5 h. The reaction was quenched with 1 Ν ΝaHCO3, diluted with dichloromethane, concentrated, and purified using 1%> methanol/20%> ethyl acetate/dichloromethane to give 150 mg (87%) of product. This material was dissolved in 0.2 mL of dichloromethane and treated with 0.5 mL of trifluoroacetic acid at 25 °C for 3 h. The reaction was quenched with 10 mL of water, made alkaline with 1 N NaHCO and extracted with ethyl acetate. This material was purified using 5%> methanol/dichloromethane (w/ 1% NH4OH) to give 109 mg (88%) of the title compound.
Example 649 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl] (isobutyl)amino]propyl} -3 -methyl-2- {3 -[(2-methyl- 1 ,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide Example 143 (59 mg, 0.198 mmol) was combined with N-hydroxysuccinimide (25 mg, 1.1 equivalents) and DCC (45 mg, 1.1 equivalents) in dichloromethane (1 mL) and stined for 1 h at 25° C. The solids are filtered, and to this mixture is added N- methylmorpholine (22 μL, 1 equivalent) and Example 625B (100 mg, 1 equivalent). The mixture was stined for 16 h, evaporated, and purified using 1.5% nιethanol/CHCl3 to give 42 mg (32%) ofthe title compound. Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.90 (m, 6 H), 1.86 (dd, J=13.90, 7.12 Hz, 1 H), 2.13 (m, 1 H), 2.69 (s, 3 H), 2.79 (m, 2 H), 2.94 (dd, J=7.46, 2.71 Hz, 2 H), 2.99 (m, 1 H), 3.04 (d, J=3.73 Hz, 1 H), 3.10 (d, J=8.48 Hz, 1 H), 3.16 (dd, J=8.82, 4.41 Hz, 1 H), 3.24 (m, 2 H), 3.59 (d, J=10.85 Hz, 1 H), 3.78 (m, 1 H), 3.85 (d, J=3.05 Hz, 1 H), 4.04 (dd, J=9.49, 5.09 Hz, 1 H), 4.42 (s, 2 H), 6.44 (d, J=8.82 Hz, 1 H), 6.92 (m, 2 H), 6.96 (s, 1 H), 7.17 (m, 5 H), 7.65 (m, 2 H). The compounds listed in Table 16, wherein X7, X , and X4 represent respectively the points of connection to the core structure (M), were prepared by coupling the conesponding acids (Examples 31-160) with the conesponding amines (Examples 625-648)as exemplified in Example 362 (Method A), Example 162 (Method B), Example 524 (Method C) and Example 4
Figure imgf000245_0001
Table 16
Figure imgf000245_0002
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Example 711 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(neopentyl)amino]propyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide Example 143D (64 mg, 0.21 mmol) was dissolved in Ν,Ν-dimethylformamide (3 mL) and treated with EDAC (66.3 mg, 2 equivalents), HOBT (58 mg, 2 equivalents), Example 26 (111 mg, 1.2 equivalents), and N-methylmorpholine (47 μL, 2 equivalents) at 25 °C for 16 h. The solvents were evaporated and the crude residue was purified by HPLC reverse phase chromatography using water (0.1%> trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 73 mg (47%) ofthe title compound.
Example 712 (2S)-N-{(lS,2R)-3-[{[4-((E)-{[(3- aminopropanoyl)oxy]imino}methyl)phenyl]sulfonyl}(isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide
Example 712 A (2S)-N-{(lS,2R)-3-[{[4-((E)-{[(3- aminopropanoyl)oxy]imino}methyl)phenyl]sulfonyl}(isobutyl)amino]-l-benzyl-2- hydroxyρropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide Example 270 (127 mg, 0.18 mmol ) was dissolved in dichloromethane (1.8 mL) and treated with Boc-β-alanine hydroxysuccinimide ester (75 mg, 1.4 equivalents), N- methylmorpholine (40 μL, 2 equivalents) and DMAP (30 mg, 1.4 equivalents) at 25 °C for 18 h. The solvents were evaporated and the crade residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 123 mg (78%>) ofthe title compound. Example 712B (2S)-N-{(lS,2R)-3-[{[4-((E)-{[(3- aminopropanoyl)oxy]imino}methyl)phenyl]sulfonyl}(isobutyl)amino]-l-benzyl-2- hydroxypropyl} -3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide Example 712 A ( 150 mg, 0.17 mmol) was dissolved in dichloromethane : trifluoroacetic acid (3 mL, 2:1) at 25 °C for 30 min. The solvents were evaporated and the crude residue was purified by HPLC reverse phase chromatography using water (0.1 %> trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 76 mg (50%) ofthe title compound.
Example 713 (2S)-N-[(lS,2R)-l-benzyl-2-hydroxy-3-(isobutylamino)propyl]-3-methyl-2-{3-[(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl} butanamide Example 713 A (2R,3iS)-3-amino-l-(isobutylamino)-4-phenyl-2-butanol Example 1 (3 g, 8.9 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (8 mL, 12 equivalents) and stined for 5 h at 25 °C. The mixture was quenched with water (50 mL), the aqueous layer was made alkaline to pH 9 with ΝaHCO3. The mixture was stined for 3 h, and the solids were filtered and dried in vacuo to give 2.5 g (100%>) ofthe diamine.
Example 713B (2S)-N-[(lS,2R)-l-benzyl-2-hydroxy-3-(isobutylamino)proρyl]-3-methyl-2-{3-[(2-methyl- 1,3 -thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl} butanamide Example 143D (1 g, 3.4 mmol) was combined with the Example 713A (1.5 g, 1.5 equivalents) in Ν,Ν-dimethylformamide (50 mL) and to this mixture was added HOBT (0.6 g, 1.5 equivalents) and EDAC (0.86 g, 1.5 equivalents). The mixture was stined for 16 h at 25 °C and quenched with NaHCO3, extracted with ethyl acetate, and evaporated. The residue was purified using 10% methanol/dichloromethane to give 1.14 g (74%) ofthe title compound.
Example 714 (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(3-methoxyphenyl)sulfonyl]amino}propyl)- 3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide Example 713B (20 mg, 0.04 mmol) was dissolved in dichloromethane (0.5 mL) and treated with triethylamine (13.7 μL, 2.5 equivalents) followed by 3-methoxybenzene sulfonyl chloride (9.8 mg, 1.2 equivalents) at 25 °C for 16 h. The solvents were evaporated, and the residue was purified using chloroform to give 20.2 mg (76%>) ofthe title compound. Η ΝMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.55 (s, 1 H), 1.84 (m, 1 H), 2.13 (m, 1 H), 2.69 (s, 3 H), 2.84 (dd, J=13.56, 6.78 Hz, 1 H), 3.01 (m, 1 H), 3.13 (m, 1 H), 3.22 (m, 1 H), 3.63 (d, J=11.19 Hz, 1 H), 3.76 (m, 1 H), 3.83 (d, J=3.05 Hz, 1 H), 3.86 (d, J=5.09 Hz, 3 H), 4.16 (m, 1 H), 4.41 (m, 2 H), 6.45 (d, J=8.82 Hz, 1 H), 6.92 (d, J=6.10 Hz, 1 H), 7.09 (m, 1 H), 7.12 (m, 1 H), 7.15 (d, J=3.73 Hz, 1 H), 7.19 (m, 5 H), 7.31 (m, 2 H), 7.38 (m, 2 H), 7.43 (m, I H). The compounds listed in Table 17, wherein X represents the point of connection to the core structure (Ν), were prepared using the procedure as exemplified in Example 714, substituting the conesponding sulfonyl chlorides for 3-methoxybenzene sulfonyl chloride:
Figure imgf000254_0001
Figure imgf000254_0002
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Example 761 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(3- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo- 1 -imidazolidinyljbutanamide Example 714 (31 mg, 0.045 mmol) in dichloromethane (3 mL) was added BBr (20 μL, 5 equivalents) and stined for 2 h at 25 °C. The mixture was quenched with IN ΝaHCO3 and extracted with ethyl acetate. The solvents were evaporated and the residue was purified using ethyl acetate to give 21 mg (69%) ofthe title compound.
Example 762 (2S)-N-{(lS,2R)-l-benzyl-3-[[(5-bromo-2-hydroxyphenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl} butanamide In a similar manner to Example 761, Example 747 was treated with BBr to give the title compound.
Example 763 (2S)-N-{(lS,2R)-l-benzyl-3-[{[4-(l,2-dihydroxyethyl)phenyl]sulfonyl}(isobutyl)amino]-2- hydroxypropyl} -3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide Example 749 (30 mg, 0.044 mmol) dissolved in tetrahydrofuran (1 L) and water (0.2 mL) was added 4% weight OsO4 in water (16.3 μL, 6 mol%) and ΝMMO (5.2 mg, 1.2 equivalents). The mixture was stined at 25 °C for 4h and quenched with 10% ΝaHSO3. The mixture was extracted with ethyl acetate, the solvents were evaporated, and the residue was purified using 5%> methanol/dichloromethane to give 21 mg (67%) ofthe title compound. Example 764 (2S)-N-{(lS,2R)-l-benzyl-3-[[(4-formylphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}- 3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide Example 749 (81 mg, 0.12 mmol) in tetrahydrofuran (3 mL) and water (0.6 mL) was added 4% weight OsO4 in water (44 μL, 6 mol%) followed by ΝaIO4 (56 mg, 2.2 equivalents). The mixture was stined at 25 °C for 16 h and quenched with 10%> NaHSO3, extracted with ethyl acetate, solvents were evaporated, and the residue was purified using ethyl acetate to give 68 mg (84%>) ofthe title compound.
Example 765 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[{[4- (hydroxymethyl)phenyl]sulfonyl}(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide Example 764 (14 mg, 0.02 mmol) was dissolved in ethanol (0.5 mL) and combined with ΝaBH4 (2.2 mg, 3 equivalent) and stined at 25 °C for 1 h. The solvents were evaporated, and the residue was purified using 5%> methanol/dichloromethane to give 9 mg (69%) ofthe title compound. Example 766 (2S)-N-{(lS,2R)-l-benzyl-3-[{[4-(formylamino)phenyl]sulfonyl}(isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide Example 650 (10 mg, 0.014 mmol) was dissolved in tetrahydrofuran (0.25 mL) and combined with formic acetic anhydride (2 drops) and the mixture was stined for 1 h. The solvent was evaporated, and the residue was purified by using 5% methanol/dichloromethane to give 8.5 mg (83%>) ofthe title compound.
Example 767 (2S)-N- {(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l -benzyl-2- hydroxypropyl} -2-(3 - { [2-(hydroxymethyl)- 1 ,3 -thiazol-4-yl]methyl} -2-oxo- 1 - imidazolidinyl)-3-methylbutanamide Example 687 (45 mg, 0.059 mmol) was dissolved in water: tetrahydrofuran (1 mL, 2:1) and treated with lithium hydroxide (8 mg, 3 equivalents) at 25 °C for 30 min. The mixture was neutralized with IN HCI (0.2 mL) and extracted with ethyl acetate. The organic layer was separated and washed with water, brine, dried over magnesium sulfate and the solvents were evaporated to give 43 mg (100%) ofthe title compound. Example 768 (2S)-N-{(lS,2R)-3-[{[3-(acetylamino)-4-hydroxyphenyl]sulfonyl}(isobutyl)amino]-l-benzyl- 2-hydroxyρropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide
Example 768A (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- nitrophenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide To 4-hydroxy-3-nitrobenzenesulfonyl chloride (69 mg, 0.27 mmol) in dichloromethane (1.2 mL) was added bistrimethylsilylacetamide (72 μL, 1 equivalent) at 25 °C for 3 h. To this mixture was added the Example 713B (150 mg, 1 equivalent) followed by triethylamine (0.12 mL, 3 equivalents). The mixture was stined for 16 h, and the solvents were evaporated. The crude residue was treated with tetrabutylammonium fluoride (TBAF) (0.9 mL, 3 equivalents IM tetrabutyl ammonium fluoride/tetrahydrofuran) for 2 h and the solvents were evaporated. The residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%>) to give 132 mg (62%) ofthe title compound.
Example 768B (2S)-N-{(lS,2R)-3-[[(3-amino-4-hydroxyphenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide Example 768A (132 mg, 0.184 mmol) in ethanol/acetic acid (2 mL, 1 : 1) is added Fe powder (40 mg, 4 equivalents) at 70 °C for 2 h. The mixture was evaporated and partitioned between CHC1 and 10%> EDTA disodium salt. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated to give 112 mg (90%> crade yield) ofthe title compound.
Example 768C
(2S)-N-{(lS,2R)-3-[{[3-(acetylamino)-4-hydroxyphenyl]sulfonyl}(isobutyl)amino]-l-benzyl- 2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl} butanamide Example 768B (20 mg, 0.029 mmol) was dissolved in dichloromethane (0.3 mL) and treated with pyridine (2 μL, 1 equivalent) and acetyl chloride (1.2 μL, 0.6 equivalent) at 25 °C for 1 h. The mixture was quenched with methanol, and the solvents were evaporated. The residue was purified by HPLC reverse phase chromatography using water (0.1 % trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 16.9 mg (75%) ofthe title compound. The compounds listed in Table 18, wherein X a, represents the points of connection to the core stracture (O), were prepared by coupling the conesponding activated acylating agents with Example 768B:
Figure imgf000260_0001
Table 18
Figure imgf000260_0002
Example 773 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl({4- [(methoxyimino)methyl]phenyl}sulfonyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide Example 764 (14.7 mg, 0.022 mmol) was dissolved in ethanol (0.5 mL) and treated with Ν,Ν-diisopropylethylamine (6.1 μL, 2.2 equivalents) and hydroxylamine-O-methyl ether hydrochloride (3.6 mg, 2 equivalents) at 25 °C for 2 h. The mixture was partitioned between IN NaHCO3 and ethyl acetate. The organic layer was evaporated, and the residue was purified using 5% methanol/chloroform to give 7.1 mg (46%) ofthe title compound.
Example 774 (2S)-N-{(lS,2R)-l-benzyl-3-[(2,3-dihydro-lH-indol-5-ylsulfonyl)(isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide Example 693 (25 mg, 0.034 mmol) was dissolved in methanol (2 mL) and treated with IN HCI (3 mL) at 60 °C for 5 h. The solvents were evaporated, and the residue was purified using 5%> methanol/dichloromethane to give 12 mg (51%) ofthe title compound. Example 775
(2S)-N-{(lS,2R)-3-[[(2-amino-4-methyl-l,3-thiazol-5-yl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl} -3-methyl-2- {3-[(2-methyl-l ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyl}butanamide Example 755 was treated in a similar manner to Example 774 to give the title compound.
Example 776 (2S)-N-{(lS,2R)-3-[({3-[(3-aminopropanoyl)amino]-4- hydroxyphenyl} sulfonyl)(isobutyl)amino]-l -benzyl-2-hydroχypropyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide Example 772 (10 mg, 0.012 mmol) was dissolved in dichloromethane (0.2 mL) and trifluoroacetic acid (0.1 mL), and the mixture was stined at 25 °C for 1 h. The solvents were evaporated, and the residue was purified by HPLC reverse phase chromatography using water (0.1%) trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%) to give 8 mg (79%) of the title compound.
Example 777 tert-butyl 2-(3- {[ {(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2- {3-[(2-methyl-l ,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanoyl)amino]-4- phenylbutyl} (isobutyl)amino]sulfonyl} anilino)-2-oxoethylcarbamate
Example 777A (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(3-nitrophenyl)sulfonyl]amino}propyl)-3- methyl-2- { 3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl} butanamide Example 713B (50 mg, 0.097 mmol) was dissolved in dichloromethane (1 mL) and treated with 3-nitrobenzenesulfonyl chloride (26 mg, 1.2 equivalents) and triethylamine (27 μL, 2 equivalents) at 25 ° for 18 h. The solvents were evaporated and the crude residue was purified using chloroform - chloroform/2%) methanol to give 66.8 mg (97%) ofthe title compound.
Example 777B tert-butyl 2-(3-{[{(2R,36)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl] -2-oxo- 1 -imidazolidinyl}butanoyl)amino]-4- phenylbutyl}(isobutyl)amino]sulfonyl}anilino)-2-oxoethylcarbamate Example 777A (66 mg, 0.094 mmol) was dissolved in ethanol: acetic acid (1 mL, 1:1) and treated with iron powder (21 mg, 4 equivalents) at 70 °C for 1.5 h. The mixture was diluted with chloroform and washed twice with 10% EDTA disodium salt. The aqueous layers were reextracted with chloroform, the organic layers combined, washed with brine, dried over magnesium sulfate, and the solvents were evaporated to give crade product amine. This amine was dissolved in dichloromethane (1 mL) and treated with Boc-glycine N- Hydroxysuccinimide ester (38 mg, 1.5 equivalents) and pyridine (0.011 mL, 1.5 equivalents) and stined at 25 °C for 18 h. The solvents were evaporated, and the crude residue was purified by HPLC reverse phase chromatography using water (0.1 %> trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%>) to give 35.3 mg (45%>) ofthe title compound. Example 778 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[{[3- (hydroxymethyl)phenyl]sulfonyl} (isobutyl)amino]propyl} -3-methyl-2- {3-[(2-methyl- 1,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide Example 758 (88 mg, 0.123 mmol) was dissolved in dichloromethane (1 mL) and treated with diisobutyl aluminum hydride (0.62 mL, 5 equivalents, IM solution in dichloromethane) at -78 °C for 1 h. The mixture was quenched with acetone (0.1 mL), warmed to 25 °C, and partitioned between dichloromethane and saturated Rochelle's salt solution. After stirring for 1 h, the organic layer was separated, dried over Νa SO4, filtered, and evaporated, and the residue was purified using ethyl acetate to give 68 mg (80%>) ofthe title compound.
Example 779 (2S)-N-{(lS,2R)-l-benzyl-3-[[(5-fomyl-2-furyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide Example 757 (103 mg, 0.134 mmol) in acetonitrile (1 mL) at 0 °C was added trimethylsilyl iodide (0.2 mL, 10 equivalents). The mixture was warmed to 25 °C for 2 h, partitioned between ethyl acetate and ΝaS2O3, and the organic layer was separated. The layer was dried over Na2SO4 and evaporated. The residue was purified using ethyl acetate to give 35 mg (39%>) ofthe title compound.
Example 780 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({5-[(E)-(hydroxyimino)methyl]-2- furyl}sulfonyl)(isobutyl)amino]propylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo- 1 -imidazolidinyl} butanamide Example 780A (2S)-N-[(lS,2R)-l-benzyl-2-hydroxy-3-(isobutyl{[5-({[(4-nitrobenzyl)oxy]imino}methyl)-2- furyl] sulfonyl} amino)propyl]-3 -methyl-2- {3- [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyl}butanamide Example 713B (50 mg, 0.097 mmol) in dichloromethane (0.5 mL) was treated with triethylamine (30 μL, 2 equivalents) followed by 5-(p-nitrobenzyloxyimino)-2-furan sulfonyl chloride (40 mg, 1.2 equivalents) at 25 °C for 16 h. The solvents were evaporated, and the residue was purified using ethyl acetate: hexanes (3:1) to give 63 mg (79%>) ofthe title compound. Example 780B (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({5-[(E)-(hydroxyimino)methyl]-2- furyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo-l-imidazolidinyl}butanamide Examples 781 (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({5-[(Z)-(hydroxyimino)methyl]-2- furyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol-4-yι)methyl]- 2-oxo-l-imidazolidinyl}butanamide Example 780A (60 mg, 0.073 mmol) was dissolved in ethano acetic acid (1:1) (1 mL), treated with iron powder (20 mg, 5 equivalents) and heated at 70 °C for 4 h. The mixture was cooled, evaporated, and partitioned between CHC13 and 10%> EDTA. The organic layer was dried over Νa2SO4, filtered, and evaporated. The residue was purified using ethyl acetate: hexanes (3:1) to give 11 mg (22%0) of Example 780B and 12 mg (24%) of Example 781.
Example 782 (2S)-N- { ( 1 S,2R)-3 - [( {4- [amino(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino] - 1 - benzyl-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2- oxoimidazolidin- 1 -yl} butanamide
Example 783 4-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo- l-imidazolidinyl}butanoyl)amino]-4-phenylbutyl}(isobutyl)amino]sulfonyl}benzamide Example 721 (33 mg, 0.048 mmol) was dissolved in ethanol (1 mL) and treated with triethylamine (70 μL, 10 equivalents) and hydroxylamine hydrochloride (14 mg, 4 equivalents). The mixture was heated at 50 °C for 3 hrs. The solvents were evaporated, and the residue was purified using 5% methanol/dichloromethane to give 13 mg (37%) of Example 782 and 8.5 mg (25%) of Example 783.
Example 784 4-{[[(2R,3S)-2-hydroxy-3-({(2S,3S)-3-methyl-2-[2-oxo-3-(3-pyridinylmethyl)-l- imidazolidinyl]pentanoyl}amino)-4-phenylbutyl](isobutyl)amino]sulfonyl}benzamide Example 785 (36 mg, 0.053 mmol) was dissolved in methanol (1 mL) and treated with triethylamine (75 μL, 10 equivalents) and hydroxylamine hydrochloride (15 mg, 4 equivalents). The mixture was heated to 80 °C for 1 h. The solvents were evaporated, and the residue was purified using 8% methanol/ethyl acetate to give 20 mg (53%>) of the p- hydroxyamidine and 4 mg (11%>) ofthe title compound.
Example 785 (2S,3S)-N-{(lS,2R)-l-benzyl-3-[[(4-cyanophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-[2-oxo-3-(3-pyridinylmethyl)-l-imidazolidinyl]pentanamide
Example 785A (2S,3S)-N-[(lS,2R)-l-benzyl-2-hydroxy-3-(isobutylamino)propyl]-3-methyl-2-[2-oxo-3-(3- pyridinylmethyl)- 1 -imidazolidinyljpentanamide Example 103 (0.266 g, 0.9 mmol) was combined with Example 713A (0.153 g, 1 equivalent) in Ν,Ν-dimethylformamide (2 mL) and to this mixture was added HOBT (0.1 g, 1.5 equivalents) and EDAC (0.15 g, 1.5 equivalents). The mixture was stined for 16 h at 25 °C and quenched with NaHCO3, extracted with ethyl acetate, and evaporated under vacuum. The residue was purified using 10% methanol/dichloromethane/0.5%) NH4OH to give 50 mg (19%) ofthe amine.
Example 785B (2S,3S)-N-{(lS,2R)-l-benzyl-3-[[(4-cyanophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-[2-oxo-3-(3-pyridinylmethyl)-l-imidazolidinyl]pentanamide Example 785A (50 mg, 0.098 mmol) was dissolved in dichloromethane (1 mL) and combined with y?-cyanobenzenesulfonyl chloride (24 mg, 1.2 equivalents) and triethylamine (41 μL, 3 equivalents) at 25 °C for 16 h. The mixture was quenched with IN ΝaHCO3 and extracted with ethyl acetate. The organic layer was evaporated, and the residue was purified using ethyl acetate to give 49 mg (74%) ofthe title compound.
Example 786 (2S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-2-{3-[(2-ethyl-l,3-thiazol-4-yl)methyl]- 2,4-dioxo-l-imidazolidinyl}-3-methylbutanamide Example 290 (75 mg, 0.23 mmol ) was combined with N-hydroxysuccinimide (24.8 mg, 1.1 equivalents) and DCC (44.5 mg, 1.1 equivalents) in dichloromethane (1 mL) and stined for 1 h at 25° C. The solids are filtered, and to this mixture was added N- methylmorpholine (24 μL, 1 equivalent) and 625B (77 mg, 1 equivalent). The mixture was stined for 16 h, evaporated, and was purified using 1% methanol/CHCl3 to give 54 mg (40%>) ofthe title compound. Η NMR (300 MHz, CDC13) δ ppm 0.79 (t, J=6.61 Hz, 6 H), 0.88 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.32 (t, J=7.63 Hz, 3 H), 1.77 (d, J=10.17 Hz, 1 H), 1.83 (m, 1 H), 2.07 (m, 1 H), 2.66 (dd, J=14.24, 10.85 Hz, 1 H), 2.83 (dd, J=13.56, 6.78 Hz, 1 H), 2.98 (m, 2 H), 3.03 (m, 1 H), 3.17 (m, 1 H), 3.27 (d, J=17.97 Hz, 1 H), 3.61 (d, J=17.97 Hz, 1 H), 3.85 (m, 2 H), 3.89 (d, J=11.19 Hz, 1 H), 4.19 (m, 1 H), 4.75 (m, 2 H), 6.33 (d, J=9.49 Hz, 2 H), 6.93 (d, J=8.82 Hz, 2 H), 7.04 (s, 1 H), 7.07 (s, 5 H), 7.66 (m, 2 H). The compounds listed in Table 19, wherein X7, X! \ , X4 represent respectively the points of connection to the core structure (P), were prepared by coupling the conesponding acids (Examples 287-359) with the amines (Examples 625-648), as exemplified in Example
Figure imgf000265_0001
Table 19
Figure imgf000265_0002
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Example 844 (2S)-N-{(lS,2R)-3-[{[4-((E)-{[(3- aminopropanoyl)oxy]imino}methyl)phenyl]sulfonyl}(cyclopentylmethyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l- imidazolidinyl} butanamide
Example 844A tert-butyl 3- {[((E)- {4-[((cyclopentylmethyl) {(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanoyl)amino]-4- phenylbutyl}amino)sulfonyl]phenyl}methylidene)amino]oxy}-3-oxopropylcarbamate Example 372 (78 mg, 0.1 mmol ) was dissolved in dichloromethane (1 mL) and treated with Boc-β-alanine hydroxysuccinimide ester (45 mg, 1.4 equivalents), Ν- methylmorpholine (25 μL, 2 equivalents) and DMAP (20 mg, 1.4 equivalents) at 25 °C for 18 h. The solvents were evaporated and the crade residue was purified by HPLC reverse phase chromatography using water (0.1%> trifluoroacetic acid): acetonitrile (95:5) to acetonitrile ' (100%) to give 62 mg (65%) ofthe title compound.
Example 844B (2S)-N-{(lS,2R)-3-[{[4-((E)-{[(3- aminopropanoyl)oxy]imino}methyl)phenyl]sulfonyl}(cyclopentylmethyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l- imidazolidinyl}butanamide Example 844A (60 mg, 0.066 mmol) was dissolved in dichloromethane: trifluoroacetic acid (3 mL, 2:1) at 25 °C for 30 min. The solvents were evaporated and the crade residue was purified by HPLC reverse phase chromatography using water (0.1 %> trifluoroacetic acid): acetonitrile (95:5) to acetonitrile (100%>) to give 46 mg (75%) ofthe title compound.
ΝMR data Example 163
Η ΝMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.44 Hz, 3 H), 0.83 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 1.53 (s, 1 H), 1.85 (m, 1 H), 2.17 (m, 1 H), 3.00 (m, 9 H), 3.66 (d, J=10.85 Hz, 1 H), 3.77 (d, J=3.39 Hz, 1 H), 3.82 (m, 1 H), 4.16 (d, J=15.26 Hz, 1 H), 4.23 (m, 1 H), 4.40 (d, J=15.60 Hz, 1 H), 6.45 (d, J=9.16 Hz, 1 H), 7.19 (m, 5 H), 7.33 (d, J=1.70 Hz, 1 H), 7.71 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (s, l H) Example 164 Η NMR (300 MHz, CDC13) δ ppm 0.76 (t, J=6.27 Hz, 6 H), 0.82 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.44 Hz, 3 H), 1.39 (d, J=9.83 Hz, 1 H), 1.75 (dd, J=14.24, 6.78 Hz, 1 H), 2.12 (m, 1 H), 2.62 (dd, J=14.41, 10.34 Hz, 1 H), 2.80 (dd, J=13.56, 6.78 Hz, 1 H), 3.05 (m, 3 H), 3.30 (m, 1 H), 3.30 (m, 1 H), 3.54 (d, J=10.85 Hz, 1 H), 3.59 (d, J=2.71 Hz, 1 H), 3.70 (m, 1 H), 3.94 (m, 2 H), 4.21 (m, 1 H), 5.92 (d, J-9.49 Hz, 1 H), 7.13 (dd, J=6.44, 2.71 Hz, 2 H), 7.24 (m, J=3.73 Hz, 3 H), 7.33 (d, J=4.07 Hz, 1 H), 7.54 (t, J=7.12 Hz, 1 H), 7.66 (d, J=8.48 Hz, 2 H), 7.70 (d, J=8.82 Hz, 2 H), 7.77 (d, J=10.85 Hz, 2 H), 8.15 (s, 1 H), 8.18 (d, J=8.48 Hz, 1 H), 8.39 (s, 1 H), 8.99 (d, J=4.41 Hz, 1 H) Example 165 Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.84 (d, J=6.44 Hz, 9 H), 1.89 (m, 1 H), 2.22 (s, 3 H), 3.01 (m, 11 H), 3.61 (d, J=10.51 Hz, 1 H), 3.95 (s, 1 H), 4.20 (m, 2 H), 4.35 (s, 2 H), 6.72 (s, 1 H), 6.93 (m, 1 H), 7.18 (m, 5 H), 7.69 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H) Example 166 Η NMR (300 MHz, CD3OD) δ ppm 0.78 (d, J=6.44 Hz, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 2.05 (m, 2 H), 2.52 (dd, J=13.90, 11.53 Hz, 1 H), 2.68 (m, 1 H), 2.97 (s, 6 H), 3.15 (m, 7 H), 3.47 (dd, J=14.58, 3.73 Hz, 1 H), 3.75 (m, 2 H), 4.11 (s, 1 H), 4.40 (d, J=15.60 Hz, 1 H), 4.63 (d, J=16.28 Hz, 1 H), 4.69 (s, 2 H), 7.16 (m, 5 H), 7.57 (s, 1 H), 7.78 (d, J=8.48 Hz, 2 H), 7.83 (d, J=8.48 Hz, 2 H), 7.95 (d, J=9.83 Hz, 1 H), 8.14 (s, 1 H) Example 167 Η NMR (300 MHz, CD3OD) δ ppm 0.78 (d, J=6.44 Hz, 6 H), 1.75 (m, 4 H), 2.00 (m, 4 H), 2.56 (m, 4 H), 2.69 (s, 3 H), 3.22 (m, 7 H), 3.74 (m, 2 H), 4.12 (m, 1 H), 4.42 (s, 2 H), 7.13 (m, 5 H), 7.78 (d, J=8.82 Hz, 2 H), 7.84 (d, J=8.82 Hz, 2 H), 7.97 (d, J=9.49 Hz, 1 H), 8.14 (s, 1 H) Example 168 Η NMR (300 MHz, CD3OD) δ ppm 0.76 (m, 6 H), 1.57 (m, 1 H), 1.89 (m, 2 H), 2.01 (m, 2 H), 2.55 (m, 2 H), 2.69 (d, L 1.36 Hz, 3 H), 3.12 (m, 6 H), 3.42 (m, J=14.92, 3.05 Hz, 1 H),
• 3.59 (m, 1 H), 3.79 (m, 4 H), 4.13 (m, 2 H), 4.42 (s, 2 H), 7.11 (m, 5 H), 7.20 (d, J=2.37 Hz, 1 H), 7.77 (d, J=7.80 Hz, 2 H), 7.83 (t, J=2.03 Hz, 2 H), 7.93 (t, J=10.17 Hz, 1 H), 8.14 (s, 1 H) Example 169 Η NMR (300 MHz, CD3OD) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.79 (d, J=6.78 Hz, 3 H), 2.03 (m, 1 H), 2.52 (m, 2 H), 2.70 (s, 3 H), 2.76 (dd, J=15.09, 10.00 Hz, 1 H), 3.02 (d, J=12.89 Hz, 6 H), 3.15 (m, 6 H), 3.57 (m, 2 H), 3.75 (d, J=l 1.19 Hz, 1 H), 4.00 (m, 3 H), 4.42 (s, 2 H), 7.12 (m, 5 H), 7.20 (s, 1 H), 7.84 (d, J=8.82 Hz, 2 H), 7.90 (d, J=8.82 Hz, 2 H), 8.06 (d, J=9.83 Hz, I H), 8.16 (s, 1 H) Example 170
Η NMR (300 MHz, CD3OD) δ ppm 0.76 (d, J=2.71 Hz, 3 H), 0.79 (m, 3 H), 1.23 (m, 1 H),
1.61 (m, 5 H), 2.04 (m, 1 H), 2.26 (dd, J=15.09, 7.29 Hz, 1 H), 2.52 (m, 1 H), 2.70 (s, 3 H),
3.13 (m, 11 H), 3.46 (dd, J=14.92, 3.73 Hz, 1 H), 3.72 (d, J=10.85 Hz, 1 H), 3.77 (m, 1 H), 4.12 (m, 1 H), 4.42 (d, J=1.36 Hz, 2 H), 7.08 (m, 3 H), 7.14 (m, 2 H), 7.21 (s, 1 H), 7.78 (d,
J=8.82 Hz, 2 H), 7.83 (d, J=8.82 Hz, 2 H), 7.96 (m, 1 H)
Example 171
Η NMR (300 MHz, CD3OD) δ ppm 0.71 (d, J=6.78 Hz, 3 H), 0.76 (d, J=6.78 Hz, 3 H), 2.02
(m, 1 H), 2.51 (m, 2 H), 2.69 (d, J=4.07 Hz, 3 H), 3.12 (m, 2 H), 3.35 (s, 3 H), 3.42 (m, 1 H), 3.70 (d, J=11.19 Hz, 1 H), 3.79 (m, 1 H), 4.09 (s, 1 H), 4.41 (m, 2 H), 4.64 (s, 2 H), 6.20 (d,
J=3.39 Hz, 1 H), 6.25 (m, 1 H), 7.08 (m, 3 H), 7.15 (m, 2 H), 7.20 (s, 1 H), 7.25 (d, J=2.71
Hz, 1 H), 7.71 (m, 4 H), 7.95 (d, J=9.83 Hz, 1 H), 8.12 (s, 1 H)
Example 172
Η NMR (300 MHz, CD3OD) δ ppm 0.78 (t, J=6.44 Hz, 6 H), 2.05 (m, 1 H), 2.48 (dd, J=13.90, 11.19 Hz, 1 H), 2.56 (m, 1 H), 2.69 (s, 3 H), 3.16 (m, 8 H), 3.70 (m, 1 H), 3.75 (s, 1
H), 3.78 (m, 1 H), 4.03 (m, 1 H), 4.41 (d, J=2.37 Hz, 2 H), 4.64 (d, J=17.63 Hz, 1 H), 4.91 (d,
J=17.63 Hz, 2 H), 7.10 (m, 5 H), 7.20 (s, 1 H), 7.83 (m, 4 H), 8.00 (d, J=8.14 Hz, 1 H), 8.17
(s, l H)
Example 173 Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.78 Hz, 3 H), 0.79 (d, J=6.78 Hz, 3 H), 0.86
(d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.87 (m, 1 H), 2.14 (m, 1 H), 2.41 (s, 3 H),
2.61 (s, 3 H), 2.70 (m, 1 H), 2.88 (dd, J=13.56, 6.78 Hz, 1 H), 2.98 (m, 1 H), 3.13 (m, 7 H),
3.62 (d, J=l 1.19 Hz, 1 H), 3.77 (m, 1 H), 4.11 (m, 1 H), 4.38 (d, J=4.07 Hz, 2 H), 6.48 (d, J=9.16 Hz, 1 H), 7.16 (m, 5 H), 7.70 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.15 (s, 1 H)
Example 174
Η NMR (300 MHz, CDC13) δ ppm 0.80 (d, J=6.44 Hz, 3 H), 0.86 (t, J=6.44 Hz, 6 H), 0.91
(d, J=6.78 Hz, 3 H), 1.53 (d, J=5.09 Hz, 1 H), 1.87 (m, J=6.44 Hz, 1 H), 2.18 (m, 1 H), 2.82
(m, 3 H), 3.09 (m, 5 H), 3.69 (d, J=11.19 Hz, 1 H), 3.79 (m, 2 H), 4.22 (m, 1 H), 4.30 (d, J=15.60 Hz, 1 H), 4.54 (d, J=15.60 Hz, 1 H), 6.48 (d, J=8.82 Hz, 1 H), 7.20 (m, 4 H), 7.52 (t,
J=7.80 Hz, 1 H), 7.59 (m, 1 H), 7.68 (s, 1 H), 7.71 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2
H), 8.09 (m, 1 H), 8.13 (m, 1 H), 8.16 (s, 1 H)
Example 175
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 1.87 (m, 1 H), 2.15 (m, 1 H), 2.96 (m, 10 H),
3.67 (d, J=10.85 Hz, 1 H), 3.78 (dd, J=8.65, 5.26 Hz, 1 H), 4.17 (dd, J=10.00, 4.58 Hz, 1 H),
4.24 (d, J=15.26 Hz, 1 H), 4.45 (d, J=15.26 Hz, 1 H), 6.53 (d, J=8.82 Hz, 1 H), 7.17 (m, 5 H), 7.30 (m, 1 H), 7.60 (m, 1 H), 7.71 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H), 8.55 (m, 2 H) Example 176
Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.82 (t, J=7.46 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 0.98 (m, 1 H), 1.29 (m, 1 H), 1.92 (m, 2 H), , 2.99 (m, 9 H), 3.75 (m, 2 H), 3.80 (s, 3 H), 3.85 (q, J=5.76 Hz, 1 H), 4.06 (m, 1 H), 4.63 (d, J=15.26 Hz, 1 H), 4.86 (d, J=15.26 Hz, 1 H), 6.45 (d, J=8.48 Hz, 1 H), 7.15 (m, 5 H), 7.33 (m, 2 H), 7.74 (m, 6 H), 8.18 (s, 1 H) Example 177 Η NMR (300 MHz, CD3OD) δ ppm 0.77 (t, J=5.76 Hz, 6 H), 2.04 (m, 1 H), 2.54 (m, 2 H), 2.71 (m, 3 H), 3.14 (m, 5 H), 3.28 (s, 3 H), 3.49 (m, 5 H), 3.73 (d, J=10.85 Hz, 1 H), 3.79 (m, 1 H), 4.07 (m, 1 H), 4.42 (d, J=1.70 Hz, 2 H), 7.12 (m, 5 H), 7.21 (s, 1 H), 7.77 (d, J=8.48 Hz, 2 H), 7.84 (d, J=8.82 Hz, 2 H), 7.98 (d, J=9.49 Hz, 1 H), 8.14 (d, J=3.39 Hz, 1 H) Example 178 Η NMR (300 MHz, CD3OD) δ ppm 0.78 (d, J=6.44 Hz, 6 H), 1.77 (m, 2 H), 2.00 (m, 2 H), 2.55 (m, 3 H), 3.12 (m, 7 H), 3.40 (m, 4 H), 3.46 (s, 3 H), 3.73 (m, 2 H), 4.12 (m, 1 H), 4.45 (s, 2 H), 4.70 (s, 2 H), 7.08 (m, 3 H), 7.15 (m, 2 H), 7.37 (s, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.83 (d, J=8.82 Hz, 2 H), 7.96 (d, J=9.49 Hz, 1 H), 8.14 (s, 1 H) Example 179 Η NMR (300 MHz, CDC13) δ ppm 0.72 (d, J=6.78 Hz, 3 H), 0.83 (m, J=7.46 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 0.97 (m, 1 H), 1.35 (m, 1 H), 1.86 (d, J=6.78 Hz, 1 H), 1.98 (m, 1 H), 2.89 (m, 4 H), 3.12 (m, 4 H), 3.74 (d, J=10.85 Hz, 1 H), 3.83 (m, 2 H), 4.20 (m, 3 H), 4.48 (d, J=15.26 Hz, 1 H), 6.53 (d, J=8.48 Hz, 1 H), 7.19 (m, 7 H), 7.37 (m, 1 H), 7.67 (d, J=7.80 Hz, 1 H), 7.71 (d, J=8.82 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H)
Example 180
Η NMR (300 MHz, CDC13) δ ppm 0.70 (d, J=6.44 Hz, 3 H), 0.85 (t, J=7.29 Hz, 3 H), 1.02 (s, 1 H), 1.36 (m, 1 H), 1.65 (dd, J=11.02, 7.97 Hz, 4 H), 1.85 (m, 2 H), 1.98 (m, 4 H), 2.52 (m, 1 H), 2.80 (dd, J=14.24, 10.17 Hz, 1 H), 2.91 (s, 1 H), 3.16 (m, 5 H), 3.72 (d, J=10.85 Hz, 1 H), 3.79 (m, 1 H), 4.20 (m, J=15.26 Hz, 2 H), 4.52 (d, J=15.60 Hz, 1 H), 6.65 (s, 1 H), 7.20 (m, 7 H), 7.45 (s, 1 H), 7.71 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 3 H), 8.16 (s, 1 H) Example 181
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.87 (m, 9 H), 1.01 (d, J=22.72 Hz, 1 H), 1.37 (m, 1 H), 1.87 (d, J=6.78 Hz, 2 H), 2.00 (m, 1 H), 2.96 (m, 9 H), 3.79 (m, J=10.85 Hz, 2 H), 4.27 (m, J=15.94 Hz, 2 H), 4.49 (d, J=15.94 Hz, 1 H), 6.53 (d, J=8.82 Hz, 1 H), 7.20 (m, 5 H), 7.30 (s, 2 H), 7.69 (d, J=8.48 Hz, 2 H), 7.80 (d, J=8.14 Hz, 2 H), 8.16 (s, 1 H), 8.60 (s, 2 H) Example 182
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.87 (t, J=7.29 Hz, 3 H), 1.03 (s, 1 H), 1.43 (s, 1 H), 1.69 (m, 2 H), 1.86 (m, 2 H), 1.98 (m, 4 H), 2.50 (m, 1 H), 2.82 (m, 1 H), 3.13 (m, 8 H), 3.82 (m, J=10.51 Hz, 2 H), 4.28 (m, J=16.62 Hz, 2 H), 4.51 (d, J=16.28 Hz, 1 H), 6.59 (d, J=8.82 Hz, 1 H), 7.21 (m, J=13.05, 4.24 Hz, 5 H), 7.34 (s, 2 H), 7.68 (d, J=8.48 Hz, 2 H), 7.80 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H), 8.61 (s, 2 H) Example 183
Η NMR (300 MHz, CD3OD) δ ppm 0.75 (m, 6 H), 1.16 (t, J=6.44 Hz, 3 H), 2.01 (m, 1 H), 2.52 (m, 2 H), 2.70 (s, 3 H), 2.91 (m, 1 H), 3.13 (m, 9 H), 3.63 (m, 1 H), 3.72 (m, 1 H), 3.89 (m, 1 H), 4.06 (m, 1 H), 4.42 (d, J=2.03 Hz, 2 H), 7.08 (m, 3 H), 7.14 (m, 2 H), 7.21 (s, 1 H), 7.78 (d, J=8.82 Hz, 2 H), 7.83 (d, J=8.82 Hz, 2 H), 8.14 (s, 1 H) Example 184
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.85 (t, J=7.29 Hz, 3 H), 1.00 (m, 2 H), 1.35 (m, 2 H), 1.66 (m, 4 H), 1.82 (m, 1 H), 1.98 (m, 4 H), 2.48 (dd, J=15.26, 7.46 Hz, 1 H), 2.81 (m, 2 H), 3.11 (m, 3 H), 3.79 (m, 2 H), 3.86 (m, 1 H), 4.24 (m, 1 H), 4.80 (t, J=15.60 Hz, 2 H), 6.60 (d, J=8.82 Hz, 1 H), 7.16 (m, 5 H), 7.27 (m, 1 H), 7.60 (m, 1 H), 7.72 (m, 4 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H), 8.17 (m, 2 H) Example 185 Η NMR (300 MHz, CD3OD) δ ppm 0.78 (d, J=6.78 Hz, 6 H), 2.07 (m, 1 H), 2.55 (m, 2 H), 2.70 (s, 3 H), 3.14 (m, 6 H), 3.43 (m, 2 H), 3.58 (m, 2 H), 3.77 (m, 2 H), 4.10 (m, 1 H), 4.42 (d, J=1.36 Hz, 2 H), 6.82 (d, J=2.37 Hz, 1 H), 6.90 (dd, J=5.09, 3.39 Hz, 1 H), 7.09 (m, 3 H), 7.18 (m, 3 H), 7.20 (s, 1 H), 7.77 (d, J=8.82 Hz, 2 H), 7.82 (d, J=8.82 Hz, 2 H), 8.02 (d, J=9.83 Hz, I H), 8.14 (s, 1 H) Example 186 Η NMR (300 MHz, DMSO-d6) δ ppm 0.61 (d, J=6.44 Hz, 3 H), 0.76 (d, J=7.46 Hz, 3 H), 0.81 (d, J=6.78 Hz, 6 H), 0.92 (m, 2 H), 1.06 (m, 1 H), 1.26 (m, 1 H), 1.76 (s, 1 H), 1.98 (d, J=6.78 Hz, 1 H), 2.40 (dd, J=13.56, 11.19 Hz, 1 H), 2.59 (m, 2 H), 2.63 (s, 3 H), 2.98 (m, 2 H), 3.13 (d, J=7.80 Hz, 1 H), 3.25 (d, J=17.29 Hz, 2 H), 3.58 (d, J=7.46 Hz, 1 H), 3.85 (m, J=10.85 Hz, 2 H), 4.31 (d, J=8.48 Hz, 2 H), 4.95 (d, J=6.44 Hz, 1 H), 7.06 (m, 5 H), 7.22 (s, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.80 (d, J=8.82 Hz, 2 H), 8.24 (s, 1 H) Example 187
Η NMR (300 MHz, DMSO-d6) δ ppm 0.63 (d, J=6.78 Hz, 3 H), 0.78 (t, J=7.12 Hz, 3 H), 0.92 (m, 2 H), 1.24 (s, 1 H), 1.60 (m, J=29.84, 8.82 Hz, 2 H), 1.73 (m, 4 H), 1.89 (m, 2 H), 2.42 (dd, J=13.73, 11.02 Hz, 1 H), 2.59 (m, 2 H), 2.64 (s, 3 H), 3.09 (m, 6 H), 3.56 (d, J=3.73 Hz, 1 H), 3.86 (d, J=10.85 Hz, 2 H), 4.32 (m, 2 H), 4.99 (d, J=6.44 Hz, 1 H), 7.06 (m, 3 H), 7.22 (s, 1 H), 7.79 (m, 4 H), 7.91 (m, 2 H), 8.24 (s, 1 H) Example 188 Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.78 Hz, 3 H), 0.85 (t, J=6.78 Hz, 6 H), 0.90 (d, J=6.44 Hz, 3 H), 0.94 (m, 1 H), 1.37 (m, 1 H), 1.85 (m, 1 H), 2.04 (s, 1 H), 2.83 (m, 4 H), 3.06 (m, 6 H), 3.83 (m, 2 H), 4.23 (s, 1 H), 4.81 (m, J=13.90 Hz, 2 H), 6.53 (d, J=8.48 Hz, 1 H), 7.16 (m, 5 H), 7.61 (t, J=7.46 Hz, 1 H), 7.74 (m, 5 H), 8.15 (m, 3 H), 8.24 (m, 2 H) Example 189
Η NMR (300 MHz, DMSO-d6) δ ppm 0.64 (d, J=6.78 Hz, 3 H), 0.79 (m, 3 H), 0.88 (m, 1 H), 1.19 (m, 1 H), 1.60 (m, 1 H), 1.73 (m, 4 H), 1.87 (dd, J=13.22, 7.80 Hz, 2 H), 2.12 (s, 3 H), 2.43 (dd, J=13.56, 10.85 Hz, 1 H), 2.57 (m, 1 H), 2.67 (m, J=7.12 Hz, 1 H), 3.09 (m, 8 H), 3.56 (s, 1 H), 3.85 (m, J=10.85 Hz, 2 H), 4.26 (t, J=15.26 Hz, 2 H), 4.99 (d, J=6.10 Hz, 1 H), 6.88 (s, 1 H), 7.07 (m, 5 H), 7.79 (m, 4 H), 7.87 (d, J=9.49 Hz, 1 H), 8.24 (s, 1 H) Example 190
Η NMR (300 MHz, DMSO-d6) δ ppm 0.62 (d, J=6.78 Hz, 3 H), 0.80 (m, 9 H), 0.89 (m, 1 H), 1.22 (m, 1 H), 1.72 (d, J=2.37 Hz, 1 H), 1.99 (m, 1 H), 2.12 (s, 3 H), 2.41 (dd, J=13.39, 11.02 Hz, 1 H), 2.67 (m, 1 H), 2.87 (dd, J=13.73, 6.61 Hz, 1 H), 3.10 (m, 6 H), 3.58 (d, J=6.10 Hz, 1 H), 3.85 (m, 2 H), 4.26 (t, J=15.26 Hz, 2 H), 4.95 (d, J=6.44 Hz, 1 H), 6.88 (s, 1 H), 7.06 (m, 5 H), 7.78 (m, 4 H), 7.88 (d, J=9.49 Hz, 1 H), 8.24 (s, 1 H) Example 191
Η NMR (300 MHz, CD3OD) δ ppm 0.72 (d, J=6.44 Hz, 3 H), 0.86 (m, 6 H), 0.91 (d, J=6.78 Hz, 3 H), 0.99 (m, 1 H), 1.32 (m, 1 H), 1.85 (m, 1 H), 2.02 (m, 1 H), 2.48 (m, 2 H), 3.07 (m, 8 H), 3.44 (dd, J=14.92, 3.39 Hz, 1 H), 3.75 (m, 1 H), 3.85 (d, J=11.19 Hz, 1 H), 4.10 (m, 1 H), 4.41 (d, J=14.58 Hz, 1 H), 4.57 (d, J=14.92 Hz, 1 H), 6.98 (dd, J=4.92, 1.87 Hz, 3 H), 7.13 (m, 2 H), 7.25 (m, 1 H), 7.59 (m, 2 H), 7.78 (d, J=8.48 Hz, 2 H), 7.84 (d, J=8.82 Hz, 2 H), 8.14 (s, 1 H), 8.16 (s, 1 H) Example 192 Η NMR (300 MHz, CD3QD) δ ppm 0.79 (m, 9 H), 0.95 (d, J=6.78 Hz, 3 H), 2.04 (m, 2 H), 2.52 (m, 1 H), 2.69 (d, J=4.07 Hz, 3 H), 3.16 (m, 7 H), 3.46 (m, 3 H), 3.73 (m, 3 H), 3.83 (m, 1 H), 4.09 (s, 1 H), 4.42 (s, 2 H), 7.11 (m, 5 H), 7.22 (m, 1 H), 7.75 (d, J=8.48 Hz, 2 H), 7.89 (d, J=8.48 Hz, 2 H), 8.14 (s, 1 H) Example 193 Η NMR (300 MHz, CD3OD) δ ppm 0.65 (dd, J=9.16, 6.78 Hz, 3 H), 0.82 (t, J=6.95 Hz, 6 H), 0.95 (d, J=6.44 Hz, 3 H), 1.89 (m, 1 H), 2.06 (m, 1 H), 2.50 (dd, J=13.73, 10.68 Hz, 1 H), 2.64 (m, 1 H), 2.70 (s, 3 H), 3.10 (m, 6 H), 3.54 (m, 1 H), 3.65 (m, 2 H), 3.76 (m, 2 H), 4.00 (m, 2 H), 4.43 (s, 2 H), 7.17 (m, 6 H), 7.73 (m, 3 H), 7.87 (m, 1 H), 8.06 (m, 1 H), 8.14 (s, 1
H) Example 194
Η NMR (300 MHz, DMSO-d6) δ ppm 0.64 (d, J=6.78 Hz, 3 H), 0.80 (m, 3 H), 0.92 (m, 1 H), 1.20 (m, 4 H), 1.53 (m, 6 H), 1.77 (d, J=3.05 Hz, 1 H), 2.25 (m, J=7.46 Hz, 1 H), 2.40 (dd, J=13.39, 11.02 Hz, 1 H), 3.09 (m, 8 H), 3.60 (s, 1 H), 3.91 (m, J=10.85 Hz, 2 H), 4.80 (d, J=3.05 Hz, 2 H), 4.96 (d, J=6.44 Hz, 1 H), 6.93 (m, 3 H), 7.05 (d, J=6.44 Hz, 2 H), 7.42 (d, J=4.41 Hz, 1 H), 7.62 (t, J=7.12 Hz, 1 H), 7.79 (m, 4 H), 7.97 (d, J=9.49 Hz, 1 H), 8.06 (d, J=7.80 Hz, 1 H), 8.24 (s, 1 H), 8.30 (d, J=7.80 Hz, 1 H), 8.89 (d, J=4.41 Hz, 1 H) Example 195
Η NMR (300 MHz, CDC13) δ ppm 0.73 (d, J=6.44 Hz, 3 H), 0.84 (dd, J=12.72, 6.95 Hz, 6 H), 0.90 (d, J=6.44 Hz, 3 H), 1.00 (m, 1 H), 1.33 (s, 1 H), 1.87 (d, J=6.78 Hz, 1 H), 1.99 (s, 1 H), 2.34 (s, 3 H), 2.75 (dd, J=14.24, 9.83 Hz, 1 H), 2.88 (m, 3 H), 3.09 (m, 6 H), 3.76 (d, J=10.85 Hz, 1 H), 3.81 (s, 1 H), 4.17 (m, 1 H), 4.28 (d, J=14.92 Hz, 1 H), 4.44 (d, J=14.92 Hz, 1 H), 6.49 (d, J=8.82 Hz, 1 H), 7.19 (m, 6 H), 7.71 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H), 8.42 (m, 2 H) Example 196
Η NMR (300 MHz, CDC13) δ ppm 0.73 (d, J=6.44 Hz, 3 H), 0.85 (m, 6 H), 0.91 (d, J=6.44 Hz, 3 H), 1.03 (m, 1 H), 1.35 (d, J=3.05 Hz, 1 H), 1.86 (m, 1 H), 1.96 (s, 1 H), 2.56 (s, 3 H), 2.74 (dd, J=14.24, 10.17 Hz, 1 H), 3.02 (m, 8 H), 3.80 (m, 2 H), 3.88 (d, J=3.39 Hz, 1 H),
4.12 (m, 1 H), 4.38 (d, J=15.60 Hz, 1 H), 4.59 (d, J=15.60 Hz, 1 H), 6.49 (d, J=8.82 Hz, 1 H), 7.06 (d, J=7.46 Hz, 2 H), 7.18 (m, 5 H), 7.58 (m, 1 H), 7.70 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (s, I H) Example 197 Η NMR (300 MHz, CDC13) δ ppm 0.73 (d, J=6.44 Hz, 3 H), 0.89 (m, 9 H), 1.01 (s, 1 H), 1.39 (s, 1 H), 1.87 (m, 1 H), 1.97 (s, 1 H), 2.75 (dd, J=14.24, 10.17 Hz, 1 H), 3.03 (m, 8 H), 3.77 (d, J=10.85 Hz, 1 H), 3.79 (s, 1 H), 3.90 (d, J=3.05 Hz, 1 H), 4.16 (s, 1 H), 4.40 (d, J=15.60 Hz, 1 H), 4.59 (d, J=15.60 Hz, 1 H), 6.53 (d, J=8.82 Hz, 1 H), 7.18 (m, 7 H), 7.70 (m, J=8.48 Hz, 3 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H), 8.56 (d, J=4.07 Hz, 1 H) Example 198
Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.78 Hz, 3 H), 0.85 (t, J=7.29 Hz, 6 H), 0.91 (d, J=6.78 Hz, 3 H), 1.01 (m, 1 H), 1.39 (m, 1 H), 1.88 (m, 1 H), 1.98 (m, 1 H), 2.75 (dd, J=14.41, 10.00 Hz, 1 H), 2.87 (dd, J=13.73, 6.95 Hz, 2 H), 2.99 (m, 1 H), 3.17 (m, 4 H), 3.48 (s, 3 H), 3.81 (m, 3 H), 4.17 (m, 1 H), 4.37 (d, J=15.60 Hz, 1 H), 4.56 (s, 2 H), 4.60 (d, J=15.94 Hz, 1 H), 6.50 (d, J=8.48 Hz, 1 H), 7.17 (m, 5 H), 7.32 (d, J=7.80 Hz, 1 H), 7.68 (m, 4 H), 7.79 (d, J=8.82 Hz, 2 H), 8.15 (s, 1 H), 8.17 (s, 1 H) Example 199
Η NMR (300 MHz, CDC13) δ ppm 0.73 (d, J=6.44 Hz, 3 H), 0.83 (t, J=7.12 Hz, 3 H), 0.98 (m, 1 H), 1.39 (m, 2 H), 1.55 (m, 6 H), 1.96 (s, 2 H), 2.13 (m, 2 H), 2.78 (m, 2 H), 3.11 (m, 7 H), 3.47 (s, 3 H), 3.80 (d, J=10.85 Hz, 1 H), 3.86 (m, 1 H), 4.20 (m, 1 H), 4.37 (d, J=15.94 Hz, 1 H), 4.56 (s, 2 H), 4.61 (d, J=15.60 Hz, 1 H), 6.66 (d, J=9.16 Hz, 1 H), 7.17 (m, 6 H), 7.33 (d, J=7.80 Hz, 1 H), 7.68 (m, 3 H), 7.79 (d, J=8.48 Hz, 2 H), 8.15 (s, 1 H) Example 200
Η NMR (300 MHz, CD3OD) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.88 (m, J=6.95, 2.20 Hz, 6 H), 0.91 (d, J=6.44 Hz, 3 H), 1.03 (m, 1 H), 1.41 (m, 1 H), 1.89 ( , 1 H), 2.02 (m, 1 H), 2.51 (dd, J=13.73, 11.36 Hz, 1 H), 2.64 (m, 1 H), 3.10 (m, 8 H), 3.45 (dd, J=14.92, 3.39 Hz, 1 H), 3.76 (m, 1 H), 3.87 (d, J=l 1.19 Hz, 1 H), 4.14 (m, 1 H), 4.53 (d, J=15.94 Hz, 1 H), 4.78 (d, J=10.17 Hz, 1 H), 7.09 (m, 3 H), 7.18 (m, 2 H), 7.47 (d, J=8.48 Hz, 1 H), 7.60 (m, 1 H), 7.76 (m, 3 H), 7.84 (d, J=8.48 Hz, 2 H), 7.92 (m, 1 H), 8.02 (m, 1 H), 8.14 (s, 1 H), 8.34 (d, J=8.48 Hz, l H) Example 201 Η NMR (300 MHz, CD3OD) δ ppm 0.73 (d, J=6.78 Hz, 3 H), 0.87 (m, 6 H), 0.91 (d, J=6.44 Hz, 3 H), 1.00 (m, 1 H), 1.30 (m, 1 H), 1.86 (m, 1 H), 2.02 (m, 1 H), 2.49 (m, 1 H), 2.58 (m, 1 H), 3.07 (m, 6 H), 3.45 (dd, J=14.92, 3.39 Hz, 1 H), 3.75 (m, 1 H), 3.84 (d, J=11.19 Hz, 1 H), 4.13 (m, 1 H), 4.31 (d, J=15.26 Hz, 1 H), 4.52 (d, J=15.60 Hz, 1 H), 7.07 (m, 3 H), 7.17 (m, 2 H), 7.59 (m, 2 H), 7.67 (m, 1 H), 7.78 (d, J=8.48 Hz, 2 H), 7.84 (d, J=8.82 Hz, 2 H), 7.98 (s, l H), 8.14 (s, 1 H) Example 202
Η NMR (300 MHz, DMSO-d6) δ ppm 0.61 (d, J=6.78 Hz, 3 H), 0.78 (dd, J=16.95, 7.12 Hz, 9 H), 0.91 (m, 1 H), 1.26 (m, 1 H), 1.73 (s, 1 H), 1.98 (m, J=6.44 Hz, 1 H), 2.39 (dd, J=13.22, 11.19 Hz, 1 H), 2.58 (t, J=7.97 Hz, 1 H), 3.05 (m, 9 H), 3.58 (m, 1 H), 3.84 (m, J=10.85 Hz, 2 H), 4.49 (m, 2 H), 7.05 (m, 5 H), 7.76 (d, J=8.82 Hz, 2 H), 7.80 (d, J=8.82 Hz, 2 H), 7.94 (s, 1 H), 8.24 (s, 1 H) Example 203
Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.82 (t, J=7.29 Hz, 3 H), 0.95 (m, 1 H), 1.24 (m, 5 H), 1.53 (m, 4 H), 1.96 (m, 1 H), 2.15 (m, 1 H), 2.99 (m, 12 H), 3.76 (d, J=11.19 Hz, 1 H), 3.88 (m, 1 H), 3.96 (d, J=2.71 Hz, 1 H), 4.11 (m, 1 H), 4.62 (d, J=14.92 Hz, 1 H), 4.86 (d, J=15.26 Hz, 1 H), 6.45 (d, J=8.82 Hz, 1 H), 7.15 (m, 5 H), 7.33 (m, 2 H), 7.74 (m, 6 H), 8.18 (s, I H) Example 204 Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.84 (t, J=7.29 Hz, 3 H), 0.98 (m, 2 H), 1.21 (m, 2 H), 1.38 (m, 2 H), 1.64 (m, 6 H), 1.97 (s, 1 H), 2.10 (m, 1 H), 2.74 (m, 3 H), 3.09 (m, 5 H), 3.81 (m, 2 H), 4.13 (m, 1 H), 5.10 (d, J=2.03 Hz, 2 H), 6.58 (d, J=8.82 Hz, 1 H), 7.13 (m, 5 H), 7.44 (dd, J=8.31, 4.24 Hz, 1 H), 7.52 (m, 1 H), 7.69 (m, 3 H), 7.77 (m, 3 H), 8.15 (s, 1 H), 8.18 (dd, J=8.31, 1.53 Hz, 1 H), 8.95 (d, J=2.37 Hz, 1 H) Example 205 Η NMR (300 MHz, CDC13) δ ppm 0.72 (s, 3 H), 0.87 (s, 9 H), 1.01 (s, 1 H), 1.40 (s, 1 H), 1.90 (m, 2 H), 2.98 (s, 11 H), 3.82 (m, 3 H), 4.17 (s, 1 H), 5.09 (m, 2 H), 7.14 (m, 5 H), 7.45 (dd, J=8.14, 4.07 Hz, 1 H), 7.52 (m, 1 H), 7.69 (m, 3 H), 7.78 (m, 3 H), 8.18 (d, J=8.14 Hz, 1 H), 8.96 (d, J=2.37 Hz, 1 H) Example 206
Η NMR (300 MHz, DMSO-d6) δ ppm 0.79 (m, J=15.77, 6.95 Hz, 6 H), 1.23 (dd, J=14.07, 6.27 Hz, 6 H), 1.32 (d, J=7.12 Hz, 6 H), 1.75 (s, 1 H), 1.96 (d, J=7.80 Hz, 1 H), 2.39 (dd, J=13.39, 11.02 Hz, 1 H), 3.07 (m, 11 H), 3.61 (m, 1 H), 3.84 (m, J=10.85 Hz, 2 H), 4.36 (m, 2 H), 4.95 (d, J=6.44 Hz, 1 H), 7.05 (m, 5 H), 7.24 (s, 1 H), 7.78 (t, J=8.82 Hz, 4 H), 7.89 (d, J=9.49 Hz, 1 H), 8.24 (s, 1 H) Example 207 Η NMR (300 MHz, DMSO-d6),. δ ppm 0.63 (d, J=6.44 Hz, 3 H), 0.77 (t, J=7.12 Hz, 3 H), 0.90 (m, 1 H), 1.23 (dd, J=14.07, 6.61 Hz, 4 H), 1.32 (d, J=6.78 Hz, 6 H), 1.52 (m, 6 H), 1.71 (d, J=16.28 Hz, 1 H), 2.26 (m, 1 H), 2.40 (dd, J=13.22, 10.85 Hz, 1 H), 2.57 (m, 1 H), 3.11 (m, 7 H), 3.59 (d, J=12.55 Hz, 1 H), 3.85 (m, J=l 1.19 Hz, 2 H), 4.30 (d, J=15.60 Hz, 1 H), 4.39 (d, J=15.26 Hz, 1 H), 4.95 (d, J=6.44 Hz, 1 H), 7.05 (m, 5 H), 7.25 (s, 1 H), 7.78 (t, J=8.82 Hz, 4 H), 7.89 (d, J=9.49 Hz, 1 H), 8.24 (s, 1 H) Example 208
Η NMR (300 MHz, DMSO-d6) δ ppm 0.66 (d, J=6.44 Hz, 3 H), 0.70 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 6 H), 1.23 (dd, J=13.73, 5.93 Hz, 6 H), 1.32 (d, J=7.12 Hz, 6 H), 1.94 (m, 1 H), 2.40 (dd, J=13.22, 11.19 Hz, 1 H), 3.00 (m, 2 H), 3.21 (m, 2 H), 3.59 (s, 1 H), 3.75 (d, J=10.85 Hz, 1 H), 3.85 (s, 1 H), 4.30 (d, J=15.26 Hz, 1 H), 4.39 (d, J=15.26 Hz, 1 H), 4.96 (d, J=6.78 Hz, 1 H), 7.05 (m, 5 H), 7.24 (s, 1 H), 7.78 (t, J=8.82 Hz, 4 H), 7.89 (d, J=9.49 Hz, 1 H), 8.24 (s, I H) Example 209 Η NMR (300 MHz, DMSO-d6), δ ppm 0.69 (t, J=7.12 Hz, 6 H), 0.85 (m, 1 H), 1.19 (m, 4 H), 1.32 (d, J=6.78 Hz, 6 H), 1.53 (m, 6 H), 1.94 (m, 1 H), 2.22 (m, 1 H), 2.40 (dd, J=13.39, 11.02 Hz, 1 H), 3.11 (m, 6 H), 3.61 (m, 1 H), 3.76 (d, J=10.85 Hz, l H), 3.88 (s, 1 H), 4.35 (dd, J=15.60, 14.92 Hz, 2 H), 4.96 (d, J=6.44 Hz, 1 H), 7.06 (m, 5 H), 7.24 (s, 1 H), 7.78 (dd, J=9.16, 8.48 Hz, 4 H), 7.88 (d, J=9.49 Hz, 1 H), 8.24 (s, 1 H) Example 210 Η NMR (300 MHz, DMSO-d6),. δ ppm 0.61 (d, J=6.44 Hz, 3 H), 0.76 (d, J=7.12 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 1.26 (d, J=5.76 Hz, 3 H), 1.73 (s, 1 H), 1.97 (s, 1 H), 2.40 (dd, J=13.39, 10.68 Hz, 1 H), 2.60 (d, J=7.46 Hz, 1 H), 2.89 (m, 1 H), 2.99 (m, 3 H), 3.01 (m, 4 H), 3.13 (d, J=8.14 Hz, 1 H), 3.23 (m, 1 H), 3.38 (s, 3 H), 3.61 (m, J=10.85 Hz, 1 H), 3.85 (m, J=l 1.19 Hz, 2 H), 4.37 (s, 1 H), 4.67 (d, J=4.07 Hz, 2 H), 4.95 (d, J=6.44 Hz, 1 H), 7.05 (m, 5 H), 7.41 (s, 1 H), 7.78 (t, J=12.21 Hz, 4 H), 7.90 (d, J=9.83 Hz, 1 H), 8.24 (s, 1 H) Example 211 Η NMR (300 MHz, DMSO-d6) δ ppm 0.63 (d, J=6.44 Hz, 3 H), 0.77 (t, J=7.29 Hz, 3 H), 0.89 (m, 1 H), 1.24 (m, 7 H), 1.56 (d, J=7.80 Hz, 6 H), 1.72 (d, J=23.06 Hz, 1 H), 2.22 (s, 1 H), 2.42 (m, 1 H), 2.60 (d, J=7.12 Hz, 1 H), 2.99 (m, 1 H), 3.13 (m, 1 H), 3.38 (s, 3 H), 3.61 (m, 2 H), 3.85 (m, J=11.19 Hz, 2 H), 4.37 (s, 2 H), 4.68 (s, 2 H), 4.95 (d, J=6.44 Hz, 1 H), 7.07 (m, 5 H), 7.41 (s, 1 H), 7.78 (m, 4 H), 7.90 (d, J=9.16 Hz, 1 H), 8.24 (s, 1 H) Example 212
Η NMR (300 MHz, CDC13) δ ppm 0.81 (m, 12 H), 1.03 (m, J=15.94 Hz, 1 H), 1.43 (m, 1 H), 1.85 (m, 1 H), 1.99 (m, 1 H), 2.35 (s, 3 H), 2.87 (m, 4 H), 3.12 (m, 7 H), 3.78 (d, J=11.19 Hz, 1 H), 3.95 (m, 1 H), 4.20 (m, J=15.94 Hz, 2 H), 4.51 (d, J=15.94 Hz, 1 H), 6.63 (d, J=7.46 Hz, 1 H), 7.14 (m, 5 H), 7.71 (m, 3 H), 7.80 (m, 3 H), 8.15 (s, 1 H), 8.55 (d, J=5.09 Hz, 1 H) Example 213
Η NMR (300 MHz, CDC13) δ ppm 0.69 (d, J=6.44 Hz, 3 H), 0.87 (m, 9 H), 0.98 (m, 1 H), 1.3,9 (m, 1 H), 1.89 (dd, J=13.73, 6.95 Hz, 1 H), 2.03 (m, 1 H), 3.02 (m, 9 H), 3.72 (m, 1 H), 3.87 (m, 1 H), 4.17 (m, 2 H), 4.44 (d, J=14.92 Hz, 1 H), 4.67 (d, J=15.26 Hz, 1 H), 6.83 (d, J=8.82 Hz, 1 H), 7.18 (m, 5 H), 7.45 (m, 2 H), 7.79 (m, 5 H), 8.10 (s, 1 H), 8.18 (s, 1 H), 8.19 (m, 1 H), 8.94 (d, J=2.71 Hz, 1 H) Example 214
Η NMR (300 MHz, CDC13) δ ppm 0.69 (d, J=6.44 Hz, 3 H), 0.87 (m, 12 H), 0.99 (m, 1 H), 1.39 (m, 1 H), 1.89 (dd, J=13.73, 6.95 Hz, 2 H), 2.02 (m, 2 H), 3.01 (m, 5 H), 3.71 (d, J=l 1.19 Hz, 1 H), 3.87 (m, 1 H), 4.17 (m, 1 H), 4.44 (d, J=14.92 Hz, 1 H), 4.66 (m, 1 H), 6.83 (d, J=8.82 Hz, 1 H), 7.18 (m, 5 H), 7.45 (m, 2 H), 7.79 (m, 5 H), 8.10 (s, 1 H), 8.20 (m, 1 H), 8.18 (s, 1 H), 8.94 (d, J=2.71 Hz, 1 H) Example 215 Η NMR (300 MHz, DMSO-d6),. δ ppm 0.62 (d, J=6.44 Hz, 3 H), 0.77 (d, J=7.46 Hz, 3 H), 0.81 (d, J=6.44 Hz, 6 H), 0.92 (m, 1 H), 1.26 (m, 2 H), 1.74 (s, 1 H), 1.98 (m, J=5.09 Hz, 1 H), 2.40 (dd, J=13.39, 11.02 Hz, 1 H), 2.60 (m, J=8.14 Hz, 1 H), 3.06 (m, 8 H), 3.58 (m, 1 H), 3.87 (d, J=10.85 Hz, 2 H), 4.47 (m, 2 H), 7.01 (m, 5 H), 7.49 (dd, J=6.44, 4.75 Hz, 1 H), 7.57 (s, 1 H), 7.78 (m, 4 H), 7.94 (m, 2 H), 8.09 (m, 1 H), 8.24 (s, 1 H) Example 216 Η NMR (300 MHz, CDC13) δ ppm 0.69 (d, J=6.78 Hz, 3 H), 0.85 (t, J=7.29 Hz, 3 H), 0.97 (m, 1 H), 1.24 (m, 3 H), 1.38 (m, 1 H), 1.55 (m, 6 H), 2.01 (m, 1 H), 2.15 (m, 1 H), 3.03 (m, 7 H), 3.72 (m, 1 H), 3.90 (m, 1 H), 4.19 (m, 2 H), 4.43 (d, J=14.92 Hz, 1 H), 4.67 (d, J=15.26 Hz, 1 H), 6.82 (d, J=8.82 Hz, 1 H), 7.16 (m, 6 H), 7.46 (m, 2 H), 7.78 (m, 5 H), 8.10 (s, 1 H), 8.20 (m, 1 H), 8.18 (s, 1 H), 8.94 (dd, J=4.41, 1.70 Hz, 1 H) Example 217
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.86 (t, J=7.29 Hz, 3 H), 1.01 (m, 1 H), 1.23 (m, 2 H), 1.38 (m, 1 H), 1.57 (m, 6 H), 2.01 (m, 1 H), 2.11 (dd, J=14.75, 7.29 Hz, 1 H), 2.99 (m, 9 H), 3.84 (m, 3 H), 4.24 (m, 1 H), 4.41 (d, J=15.26 Hz, 1 H), 4.63 (d, J=14.92 Hz, 1 H), 6.58 (d, J=8.82 Hz, 1 H), 7.17 (m, 5 H), 7.42 (dd, J=8.31, 4.24 Hz, 1 H), 7.62 (dd, J=8.48, 2.03 Hz, 1 H), 7.69 (m, 3 H), 7.79 (d, J=8.82 Hz, 2 H), 8.12 (dd, J=8.82, 6.78 Hz, 2 H), 8.16 (s, 1 H), 8.91 (d, J=3.05 Hz, 1 H) Example 218
Η NMR (300 MHz, DMSO-d6),. δ ppm 0.62 (t, J=6.61 Hz, 3 H), 0.76 (d, J=7.46 Hz, 3 H), 0.81 (d, J=6.78 Hz, 6 H), 0.91 (m, 1 H), 1.24 (m, 2 H), 1.73 (t, J=10.51 Hz, 1 H), 1.98 (m, 1 H), 2.41 (dd, J=13.22, 11.19 Hz, 1 H), 2.63 (t, J=7.63 Hz, 1 H), 2.87 (dd, J=13.56, 6.44 Hz, 1 H), 3.00 (s, 6 H), 3.14 (m, 6 H), 3.56 (m, 1 H), 3.85 (d, J=11.19 Hz, 2 H), 4.32 (s, 2 H), 4.95 (d, J=6.44 Hz, 1 H), 7.05 (m, 5 H), 7.33 (s, 1 H), 7.78 (m, 4 H), 7.90 (d, J=9.49 Hz, 1 H), 8.24 (s, 1 H). Example 219
Η NMR (300 MHz, CD3OD) δ ppm 0.71 (d, J=6.78 Hz, 3 H), 0.85 (t, J=7.29 Hz, 3 H), 1.00 (s, 9 H), 1.37 (m, 1 H), 1.89 (s, 1 H), 2.56 (dd, J=14.07, 11.02 Hz, 1 H), 3.15 (m, 7 H), 3.39 (m, 2 H), 3.48 (m, 1 H), 3.81 (d, J=11.19 Hz, 1 H), 3.91 (m, 1 H), 4.02 (m, 2 H), 4.07 (s, 3 H), 4.74 (d, J=16.95 Hz, 1 H), 5.01 (d, J=16.95 Hz, 1 H), 7.13 (m, 5 H), 7.66 (m, 2 H), 7.78 (m, 3 H), 7.83 (d, J=8.48 Hz, 2 H), 7.89 (m, 1 H), 8.14 (s, 1 H) Example 220 Η NMR (300 MHz, CD3OD) δ ppm 0.65 (d, J=6.44 Hz, 3 H), 0.73 (d, J=6.78 Hz, 3 H), 0.96 (m, 2 H), 1.97 (m, 1 H), 2.45 (m, 2 H), 2.69 (s, 3 H), 3.12 (m, 4 H), 3.52 (m, 3 H), 3.98 (s, 1 H), 4.41 (m, 2 H), 4.69 (dd, J=36.11, 16.11 Hz, 2 H), 7.08 (m, 5 H), 7.19 (s, 1 H), 7.62 (d, J=8.48 Hz, 2 H), 7.87 (m, 7 H), 8.15 (s, 1 H), 8.28 (d, J=8.14 Hz, 1 H), 8.53 (m, 1 H), 8.78 (d, J=4.75 Hz, 1 H) Example 221 Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.86 (t, J=7.29 Hz, 3 H), 1.02 (m, 1 H), 1.12 (s, 2 H), 1.44 (m, 8 H), 2.00 (s, 1 H), 2.10 (m, 1 H), 2.35 (s, 3 H), 2.87 (dd, J=14.24, 10.17 Hz, 1 H), 3.01 (dd, J=11.19, 7.80 Hz, 2 H), 3.12 (m, 5 H), 3.26 (m, 1 H), 3.79 (d, J=10.85 Hz, 1 H), 3.99 (s, 1 H), 4.18 (m, 2 H), 4.51 (d, J=15.94 Hz, 1 H), 6.63 (m, 1 H), 7.10 (dd, J=5.09, 1.70 Hz, 1 H), 7.18 (m, 5 H), 7.71 (m, J=8.31, 8.31 Hz, 3 H), 7.79 (d, J=8.48 Hz, 2 H), 8.15 (s, 1 H), 8.55 (d, J=5.09 Hz, 1 H) Example 222
Η NMR (300 MHz, CD3OD) δ ppm 0.72 (d, J=6.44 Hz, 3 H), 0.86 (m, J=12.21, 6.78 Hz, 6 H), 0.91 (d, J=6.44 Hz, 3 H), 1.00 (m, 1 H), 1.36 (s, 1 H), 1.89 (s, 1 H), 1.99 (d, J=15.26 Hz, 1 H), 2.28 (s, 3 H), 2.49 (m, J=13.73, 11.36 Hz, 1 H), 2.60 (m, J=8.48 Hz, 1 H), 3.00 (m, 1 H), 3.09 (m, 6 H), 3.08 (m, 1 H), 3.18 (m, 1 H), 3.44 (d, J=18.65 Hz, 1 H), 3.75 (m, 1 H),
3.83 (d, J=11.53 Hz, 1 H), 4.12 (m, 1 H), 4.37 (d, J=15.60 Hz, 1 H), 4.63 (m, 1 H), 7.12 (m, 5 H), 7.26 (d, J=7.80 Hz, 1 H), 7.75 (m, 3 H), 7.84 (d, J=8.48 Hz, 2 H), 8.15 (s, 1 H) Example 223
Η NMR (300 MHz, CD3OD) δ ppm 0.73 (d, J=6.78 Hz, 3 H), 0.86 (dd, J=9.16, 7.12 Hz, 6 H), 0.91 (d, J=6.44 Hz, 3 H), 1.03 (d, J=10.85 Hz, 1 H), 1.35 (s, 1 H), 1.87 (s, 1 H), 2.02 (m, 1 H), 2.17 (d, J=6.10 Hz, 3 H), 2.50 (dd, J=13.73, 11.36 Hz, 1 H), 2.63 (m, 1 H), 3.07 (m, 8 H), 3.11 (s, 3 H), 3.44 (dd, J=14.92, 3.05 Hz, 1 H), 3.75 (dd, J=15.60, 3.73 Hz, 1 H), 3.82 (dd, J=11.19, 2.71 Hz, 1 H), 4.10 (m, J=6.78 Hz, 1 H), 4.35 (d, J=15.94 Hz, 1 H), 4.58 (d, J=15.60 Hz, 1 H), 4.68 (s, 2 H), 7.13 (m, 5 H), 7.24 (m, 1 H), 7.80 (m, 5 H), 7.95 (d, J=9.83 Hz, l H), 8.14 (s, I H) Example 224 Η NMR (300 MHz, CD3OD) δ ppm 0.71 (d, J=6.78 Hz, 3 H), 0.85 (m, J=14.75, 6.95 Hz, 6 H), 0.91 (d, J=6.78 Hz, 3 H), 0.96 (m, 1 H), 1.34 (m, 1 H), 1.86 (m, J=17.97 Hz, 1 H), 2.01 (m, 1 H), 2.49 ( , 2 H), 3.08 (m, 9 H), 3.28 (s, 3 H), 3.44 (dd, J=14.58, 3.39 Hz, 1 H), 3.73 (m, 1 H), 3.81 (d, J=11.19 Hz, 1 H), 4.10 (m, 1 H), 4.21 (d, J=6.10 Hz, 1 H), 4.57 (m, 2 H), 6.40 (s, 1 H), 7.13 (m, 5 H), 7.78 (d, J-8.48 Hz, 2 H), 7.84 (m, J=8.48 Hz, 2 H), 8.15 (s, 1 H) Example 225
Η NMR (300 MHz, DMSO-d6),. δ ppm 0.62 (d, J=6.44 Hz, 3 H), 0.77 (d, J=7.12 Hz, 3 H), 0.81 (d, J=6.78 Hz, 6 H), 0.89 (m, 1 H), 1.28 (m, 1 H), 1.74 (s, 1 H), 1.96 (m, 1 H), 2.40 (dd, J=13.39, 11.02 Hz, 1 H), 2.61 (m, 1 H), 3.06 (m, 10 H), 3.59 (m, 1 H), 3.87 (d, J=10.85 Hz, 1 H), 4.48 (s, 2 H), 7.01 (m, 5 H), 7.56 (m, 1 H), 7.60 (s, 1 H), 7.76 (d, J=9.16 Hz, 2 H), 7.81 (d, J=8.82 Hz, 2 H), 7.92 (d, J=9.49 Hz, 1 H), 8.24 (s, 1 H), 8.31 (s, 1 H), 8.33 (m, 1 H), 8.67 (dd, J=4.75, 1.70 Hz, 1 H), 9.15 (d, J=1.70 Hz, 1 H) Example 226
Η NMR (300 MHz, CD3OD) δ ppm 0.73 (d, J=6.78 Hz, 3 H), 0.84 (m, 6 H), 0.91 (d, J=6.44 Hz, 3 H), 0.99 (m, 1 H), 1.39 (m, 1 H), 1.90 (m, 1 H), 2.03 (m, 1 H), 2.49 (dd, J=13.73, 11.36 Hz, 1 H), 2.62 (m, 1 H), 3.11 (m, 8 H), 3.44 (dd, J=14.92, 3.39 Hz, 1 H), 3.75 (m, 1 H), 3.85 (d, J=11.19 Hz, 1 H), 4.13 (m, 1 H), 4.46 (d, J=15.94 Hz, 1 H), 4.71 (d, J=15.94 Hz, 1 H), 7.09 (m, 5 H), 7.37 (d, J=6.78 Hz, 1 H), 7.43 (m, 1 H), 7.78 (d, J=8.82 Hz, 2 H), 7.84 (d, J=6.78 Hz, 2 H), 7.92 (m, 2 H), 8.14 (s, 1 H), 8.23 (d, J=7.12 Hz, 1 H), 8.41 (d, J=8.14 Hz, 1 H), 8.63 (m, 1 H) Example 227
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.85 (dd, J=8.99, 6.95 Hz, 6 H), 0.90 (d, J=6.44 Hz, 3 H), 1.01 (m, 1 H), 1.33 (m, 1 H), 1.85 (m, 1 H), 1.99 (m, 1 H), 2.75 (s, 3 H), 2.99 (m, 9 H), 3.83 (m, 3 H), 4.22 (dd, J=9.49, 4.75 Hz, 1 H), 4.68 (d, J=15.60 Hz, 1 H), 4.82 (d, J=15.26 Hz, 1 H), 6.54 (d, J=8.82 Hz, 1 H), 7.17 (m, 5 H), 7.51 (t, J=7.63 Hz, 1 H), 7.69 (m, 4 H), 7.79 (d, J=8.48 Hz, 2 H), 8.08 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H) Example 228 Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.78 Hz, 3 H), 0.86 (dd, J=7.12, 3.39 Hz, 6 H), 0.90 (d, J=6.44 Hz, 3 H), 1.03 (m, 1 H), 1.41 (m, 1 H), 1.87 (m, 1 H), 1.99 (m, 1 H), 2.67 (s, 3 H), 2.76 (m, 1 H), 2.88 (m, 1 H), 2.99 (m, 1 H), 3.15 (m, 5 H), 3.81 (m, 3 H), 3.89 (d, J=3.39 Hz, 1 H), 4.16 (m, 1 H), 4.51 (d, J=15.26 Hz, 1 H), 4.78 (d, J=15.26 Hz, 1 H), 6.56 (d, J=8.82 Hz, 1 H), 7.17 (m, 6 H), 7.56 (t, J=7.12 Hz, 1 H), 7.72 (m, 3 H), 7.79 (d, J=8.48 Hz, 2 H), 7.98 (d, J=7.46 Hz, 1 H), 8.07 (d, J=8.48 Hz, 1 H), 8.17 (s, 1 H) Example 229
Η NMR (300 MHz, CDC13) δ ppm 0.73 (d, J=6.44 Hz, 3 H), 0.88 (m, 9 H), 1.29 (m, 6 H), 1.87 (s, 2 H), 2.97 (m, 12 H), 3.75 (d, J=11.53 Hz, 2 H), 3.86 (d, J=3.39 Hz, 1 H), 4.12 (q, J=7.12 Hz, 1 H), 4.39 (s, 1 H), 4.58 (s, 1 H), 6.50 (d, J=8.82 Hz, 1 H), 7.08 (s, 2 H), 7.19 (s, 5 H), 7.69 (m, J=7.80 Hz, 3 H), 7.78 (d, J=8.48 Hz, 2 H), 8.15 (s, 1 H) Example 230
Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.78 Hz, 3 H), 0.86 (m, 3 H), 1.00 (m, 1 H), 1.16 (m, 2 H), 1.26 (m, J=7.29, 7.29 Hz, 1 H), 1.39 (m, 2 H), 1.64 (m, 6 H), 1.97 (m, J=11.53 Hz, 1 H), 2.13 (m, 1 H), 2.55 (s, 3 H), 2.79 (m, 2 H), 3.10 (m, 5 H), 3.79 (m, 3 H), 4.15 (m, 1 H), 4.40 (m, 1 H), 4.59 (d, J=15.60 Hz, 1 H), 6.52 (d, J=8.82 Hz, 1 H), 7.06 (d, J=7.12 Hz, 2 H), 7.16 (m, 1 H), 7.21 (m, 4 H), 7.58 (m, 1 H), 7.70 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (s, I H) Example 231 Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.84 (t, L 7.46 Hz, 3 H), 0.99 (m, 1 H), 1.15 (s, 1 H), 1.34 (m, 2 H), 1.59 (m, 6 H), 1.96 (m, 1 H), 2.11 (m, J=7.80 Hz, 1 H), 2.34 (s, 3 H), 2.80 (m, 3 H), 3.04 (m, 7 H), 3.79 (m, 2 H), 4.22 (m, 1 H), 4.28 (d, J=15.26 Hz,
1 H), 4.44 (d, J=14.92 Hz, 1 H), 6.51 (d, J=8.82 Hz, 1 H), 7.17 (m, 6 H), 7.71 (d, J=8.48 Hz,
2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H), 8.41 (m, 2 H) Example 232
Η NMR (300 MHz, CDC13) δ ppm 0.72 (d, J=6.62 Hz, 3 H), 0.85 (m, 6 H), 0.90 (d, J=6.25 Hz, 3 H), 1.00 (m, 1 H), 1.85 (m, 1 H), 1.95 (m, 1 H), 2.99 (m, 11 H), 3.40 (s, 3 H), 3.76 (d, J=11.03 Hz, 1 H), 3.82 (m, 1 H), 4.16 (m, 1 H), 4.38 (d, J=15.44 Hz, 1 H), 4.44 (s, 2 H), 4.58 (d, J=15.44 Hz, 1 H), 6.62 (d, J=8.82 Hz, 1 H), 7.17 (m, 7 H), 7.70 (d, J=8.46 Hz, 2 H), 7.80 (d, J=8.46 Hz, 2 H), 8.15 (s, 1 H), 8.50 (d, J=5.15 Hz, 1 H) Example 233
Η NMR (300 MHz, CD3OD) δ ppm 0.87 (m, 6 H), 0.91 (s, 9 H), 1.29 (d, J=2.94 Hz, 1 H), 2.02 (m, 1 H), 2.26 (m, 1 H), 2.43 (dd, J=13.79, 11.58 Hz, 1 H), 3.06 (m, 8 H), 3.43 (dd, J=14.71, 3.31 Hz, 1 H), 3.74 (m, 1 H), 4.07 (m, 1 H), 4.58 (s, 2 H), 7.10 (m, 5 H), 7.58 (s, 1 H), 7.78 (m, 5 H), 7.96 (m, 1 H), 8.14 (s, 1 H), 8.60 (m, 1 H), 8.68 (m, 1 H) Example 234 Η NMR (300 MHz, CDC13) δ ppm 0.88 (d, J=6.62 Hz, 3 H), 0.91 (d, J=6.62 Hz, 3 H), 0.98 (s, 9 H), 1.82 (m, 2 H), 2.54 (q, J=9.19 Hz, 1 H), 2.67 (dd, J=14.34, 10.30 Hz, 1 H), 3.04 (m, 5 H), 3.31 (m, 1 H), 3.82 (m, 2 H), 4.07 (s, 1 H), 4.24 (m, 1 H), 4.81 (s, 2 H), 6.26 (d, J=8.82 Hz, 1 H), 7.04 (m, 5 H), 7.28 (d, J=4.41 Hz, 1 H), 7.61 (m, 1 H), 7.72 (m, 3 H), 7.80 (d, J=8.46 Hz, 2 H), 8.17 (m, 3 H), 8.89 (d, J=4.41 Hz, 1 H) Example 235
Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.62 Hz, 3 H), 0.84 (t, J=7.35 Hz, 3 H), 0.97 (m, 2 H), 1.31 (m, 4 H), 1.61 (s, 8 H), 1.96 (s, 1 H), 2.11 (dd, J=15.08, 7.35 Hz, 1 H), 2.79 (m, 1 H), 3.06 (m, 5 H), 3.79 (m, 2 H), 4.22 (m, 2 H), 4.45 (d, J=15.08 Hz, 1 H), 6.50 (d, J=8.82 Hz, 1 H), 7.17 (m, 5 H), 7.29 (m, 1 H), 7.60 (m, 1 H), 7.71 (d, J=8.46 Hz, 2 H), 7.79 (d, J=8.82 Hz, 2 H), 8.16 (s, 1 H), 8.54 (m, 2 H) Example 236
Η NMR (300 MHz, CDC13) δ ppm 0.88 (d, J=6.62 Hz, 3 H), 0.92 (d, J=6.62 Hz, 3 H), 0.96 (s, 9 H), 1.87 (m, 1 H), 2.59 (q, J=8.95 Hz, 1 H), 2.70 (dd, J=14.16, 10.48 Hz, 1 H), 3.01 (m, 6 H), 3.32 (m, 1 H), 3.79 (m, 1 H), 4.00 (s, 1 H), 4.23 (m, 2 H), 4.46 (d, J=15.08 Hz, 1 H), 6.24 (d, J=9.19 Hz, 1 H), 7.13 (m, 5 H), 7.30 (dd, J=7.35, 4.41 Hz, 1 H), 7.62 (m, 1 H), 7.72 (d, J=8.46 Hz, 2 H), 7.80 (d, J=8.46 Hz, 3 H), 8.17 (s, 1 H), 8.55 (m, 2 H) Example 237 Η NMR (300 MHz, DMSO-d6),. δ ppm 0.61 (d, J=6.62 Hz, 3 H), 0.76 (d, J=7.35 Hz, 3 H), 0.81 (d, J=6.62 Hz, 6 H), 0.91 (m, 1 H), 1.22 (m, 1 H), 1.73 (s, 1 H), 1.96 (dd, J=13.42, 6.07 Hz, 1 H), 2.04 (s, 2 H), 2.07 (s, 1 H), 2.40 (dd, J=13.24, 11.03 Hz, 1 H), 2.61 (m, J=7.35 Hz, 1 H), 2.92 (m, 6 H), 3.03 (s, 3 H), 3.15 (m, 1 H), 3.24 (m, 1 H), 3.58 (m, 1 H), 3.84 (d, J=11.03 Hz, 1 H), 4.02 (m, 1 H), 4.37 (m, 2 H), 4.71 (s, 1 H), 4.83 (s, 1 H), 7.06 (m, 5 H), 7.35 (m, 1 H), 7.79 (t, J=8.82 Hz, 4 H), 7.90 (d, J=9.19 Hz, 1 H), 8.24 (s, 1 H) Example 238
Η NMR (300 MHz, CDC13) δ ppm 0.88 (d, J=6.62 Hz, 3 H), 0.91 (d, J=6.62 Hz, 3 H), 0.98 (s, 9 H), 1.86 (m, 1 H), 2.53 (m, 1 H), 2.67 (dd, J=14.34, 10.30 Hz, 1 H), 2.75 (s, 3 H), 3.07 (m, 7 H), 3.81 (m, 2 H), 4.07 (s, 1 H), 4.24 (m, 1 H), 4.74 (d, J=16.18 Hz, 2 H), 6.23 (d, J=8.82 Hz, 1 H), 7.05 (m, 5 H), 7.18 (s, 1 H), 7.52 (t, J=7.72 Hz, 1 H), 7.71 (m, 3 H), 7.80 (d, J=8.46 Hz, 2 H), 8.09 (t, J=9.38 Hz, 2 H), 8.17 (s, 1 H) Example 239
Η NMR (300 MHz, CDC13) δ ppm 0.88 (d, J=6.62 Hz, 3 H), 0.91 (d, J=6.62 Hz, 3 H), 0.98 (s, 9 H), 1.87 (m, 1 H), 2.67 (m, 2 H), 3.01 (m, 5 H), 3.34 (m, 1 H), 3.83 (m, 2 H), 4.06 (s, 2 H), 4.24 (m, 1 H), 4.45 (d, J=15.08 Hz, 1 H), 4.65 (d, J=15.08 Hz, 1 H), 6.31 (d, J=8.82 Hz, 1 H), 7.14 (m, 5 H), 7.42 (dd, J=8.27, 4.23 Hz, 1 H), 7.65 (m, 1 H), 7.71 (d, J=8.82 Hz, 2 H), 7.79 (d, J=8.46 Hz, 2 H), 8.14 (dd, J=8.64, 3.13 Hz, 2 H), 8.18 (s, 1 H), 8.88 (s, 1 H), 8.91 (dd, J=4.23, 1.65 Hz, 1 H) Example 240
Η NMR (300 MHz, CDC13) δ ppm 0.87 (d, J=6.62 Hz, 3 H), 0.91 (d, J=6.62 Hz, 3 H), 0.98 (s, 9 H), 1.89 (m, 1 H), 2.71 (m, 2 H), 3.04 (m, 6 H), 3.35 (m, 1 H), 3.84 (m, 1 H), 4.04 (m, J=4.78 Hz, 2 H), 4.22 (m, 1 H), 4.50 (d, J=15.08 Hz, 1 H), 4.65 (d, J=15.08 Hz, 1 H), 6.41 (d, J=8.82 Hz, 1 H), 7.14 ( , 5 H), 7.43 (dd, J=8.27, 4.23 Hz, 1 H), 7.50 (dd, J=8.46, 1.47 Hz, 1 H), 7.73 (d, J=8.46 Hz, 2 H), 7.80 (d, J=8.46 Hz, 2 H), 8.05 (s, 1 H), 8.17 (d, J=4.78 Hz, 2 H), 8.94 (dd, J=4.41, 1.47 Hz, 1 H), 9.03 (s, 1 H) Example 241 Η NMR (300 MHz, CD3OD) δ ppm 0.88 (d, J=6.99 Hz, 6 H), 0.92 (s, 9 H), 2.02 (m, 1 H), 2.22 (m, 1 H), 2.42 (dd, J=13.60, 11.77 Hz, 1 H), 3.12 (m, 8 H), 3.42 (dd, J=15.08, 3.31 Hz, 1 H), 3.73 (m, 1 H), 4.00 (s, 1 H), 4.05 (m, 1 H), 4.54 (m, 2 H), 7.05 (m, 5 H), 7.43 (m, 1 H), 7.49 (s, 1 H), 7.77 (d, J=8.82 Hz, 2 H), 7.84 (d, J=8.46 Hz, 2 H), 7.90 (m, 1 H), 8.14 (s, 1 H), 8.21 (d, J=8.09 Hz, 1 H), 8.57 (m, 1 H) Example 242 Η NMR (300 MHz, DMSO-d6),. δ ppm 0.61 (d, J=6.62 Hz, 3 H), 0.77 (m, 3 H), 0.81 (d, J=6.62 Hz, 6 H), 0.92 (m, 1 H), 1.21 (m, 2 H), 1.73 (m, 1 H), 1.97 (m, 1 H), 2.08 (s, 3 H), 2.40 (dd, J=13.42, 10.85 Hz, 1 H), 2.60 (m, 1 H), 2.94 (m, 4 H), 3.13 (m, 1 H), 3.25 (dd, J=14.52, 2.76 Hz, 1 H), 3.57 (m, 2 H), 3.86 (m, 2 H), 4.38 (s, 2 H), 5.32 (s, 2 H), 7.05 (m, 5 H), 7.47 (s, 1 H), 7.78 (m, 4 H), 7.91 (d, J=9.56 Hz, 1 H), 8.24 (s, 1 H) Example 243
Η NMR (300 MHz, CDC13) δ ppm 0.87 (d, J=6.62 Hz, 3 H), 0.92 (d, J=6.62 Hz, 3 H), 0.97 (s, 9 H), 1.53 (s, 1 H), 1.84 (m, 1 H), 2.61 (q, J=9.19 Hz, 1 H), 2.71 (dd, J=14.34, 10.30 Hz, 1 H), 2.87 (dd, J=13.42, 6.80 Hz, 1 H), 3.09 (m, 5 H), 3.34 (m, 1 H), 3.48 (s, 3 H), 3.79 (m, 1 H), 4.00 (s, 1 H), 4.16 (m, 1 H), 4.39 (d, J=15.81 Hz, 1 H), 4.57 (s, 2 H), 4.64 (d, J=15.81 Hz, 1 H), 6.18 (d, J=9.19 Hz, 1 H), 7.15 (m, 5 H), 7.33 (d, J=7.72 Hz, 1 H), 7.68 (m, 2 H), 7.72 (d, J=6.25 Hz, 2 H), 7.80 (d, J=8.46 Hz, 2 H), 8.16 (s, 1 H) Example 244
Η NMR (300 MHz, CDC13) δ ppm 0.87 (d, J=7.35 Hz, 3 H), 0.91 (d, J=6.62 Hz, 3 H), 0.95 (s, 9 H), 1.86 (m, 1 H), 2.58 (q, J=8.95 Hz, 1 H), 2.69 (dd, J=13.97, 10.30 Hz, 1 H), 2.86 (dd, J=13.42, 6.80 Hz, 1 H), 3.01 (m, 1 H), 3.13 (m, 3 H), 3.32 (m, 1 H), 3.49 (s, 3 H), 3.76 (m, 2 H), 3.98 (s, 1 H), 4.18 (m, 1 H), 4.43 (d, J=14.71 Hz, 1 H), 4.52 (d, J=15.44 Hz, 1 H), 4.70 (d, J=2.57 Hz, 2 H), 6.19 (d, J=8.82 Hz, 1 H), 7.11 (s, 1 H), 7.15 (m, 5 H), 7.71 (d, J=8.46 Hz, 2 H), 7.79 (d, J=8.82 Hz, 2 H), 7.93 (s, 1 H), 8.16 (s, 1 H) Example 245 Η NMR (300 MHz, CD3OD) δ ppm 0.71 (d, J=6.62 Hz, 3 H), 0.81 (t, J=7.35 Hz, 3 H), 0.88 (d, J=6.62 Hz, 3 H), 0.91 (d, J=6.25 Hz, 3 H), 0.99 (m, 1 H), 1.30 (m, 1 H), 1.85 (t, J=15.08 Hz, 1 H), 2.01 (m, J=14.71 Hz, 1 H), 2.48 (m, 2 H), 3.07 (m, 8 H), 3.44 (dd, J=14.89, 3.49 Hz, 1 H), 3.74 (m, 1 H), 3.85.(d, J=11.03 Hz, 1 H), 4.10 (m, 1 H), 4.38 (d, J=15.08 Hz, 1 H), 4.56 (d, J=15.08 Hz, 1 H), 7.02 (m, 3 H), 7.12 (m, 2 H), 7.38 (d, J=7.35 Hz, 1 H), 7.52 (m, 2 H), 7.61 (m, 2 H), 7.78 (d, J=8.82 Hz, 2 H), 7.83 (d, J=9.93 Hz, 2 H), 8.08 (m, 1 H), 8.14 (s, 1 H), 8.52 (dd, J=4.96, 1.65 Hz, 1 H), 8.79 (d, J=3.31 Hz, 1 H) Example 246 Η NMR (300 MHz, DMSO-d6) δ ppm 0.82 (t, J=2.94 Hz, 15 H), 1.23 (m, 1 H), 1.47 (d, J=7.35 Hz, 3 H), 1.88 (s, 3 H), 1.97 (m, 1 H), 2.17 (q, J=8.95 Hz, 1 H), 2.33 (m, 1 H), 3.05 (m, 6 H), 3.53 (t, J=8.27 Hz, 1 H), 3.84 (m, 1 H), 3.96 (s, 1 H), 4.30 (d, J=15.44 Hz, 1 H), 4.42 (d, J=15.44 Hz, 1 H), 4.95 (d, J=6.62 Hz, 1 H), 5.14 (m, 1 H), 7.03 (m, 5 H), 7.27 (s, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.80 (d, J=8.82 Hz, 2 H), 7.98 (d, J=9.56 Hz, 1 H), 8.23 (s, 1 H), 8.62 (d, J=7.72 Hz, 1 H) Example 247 Η NMR (300 MHz, CD3OD) δ ppm 0.87 (m, 6 H), 0.91 (s, 9 H), 2.00 (dd, J=14.52, 6.80 Hz, 1 H), 2.28 (m, 1 H), 2.44 (dd, J=13.42, 11.58 Hz, 1 H), 2.73 (s, 3 H), 3.10 (m, 9 H), 3.43 (dd, J=14.89, 3.49 Hz, 1 H), 3.73 (m, 1 H), 4.00 (s, 1 H), 4.03 (s, 1 H), 4.57 (s, 2 H), 7.06 (m, 5 H), 7.61 (s, 1 H), 7.78 (m, 2 H), 7.83 (d, J=8.46 Hz, 2 H), 7.96 (m, 1 H), 8.14 (s, 1 H), 8.69 (dd, J=8.46, 2.21 Hz, 1 H) Example 248 Η NMR (300 MHz, CD3OD) δ ppm 0.88 (m, 6 H), 0.91 (s, 9 H), 1.99 (s, 1 H), 2.28 (d, J=8.46 Hz, 1 H), 2.44 (m, 1 H), 3.06 (m, 8 H), 3.41 (d, J=3.68 Hz, 1 H), 3.73 (s, 1 H), 4.00 (s, 1 H), 4.07 (m, 1 H), 4.59 (s, 2 H), 7.07 (m, 5 H), 7.72 (s, 1 H), 7.77 (d, J=8.46 Hz, 2 H), 7.82 (m, 3 H), 7.94 (s, 1 H), 8.14 (s, 1 H), 8.21 (m, 1 H), 8.74 (m, 1 H) Example 249 Η NMR (300 MHz, CD3OD) δ ppm 0.88 (d, J=6.99 Hz, 6 H), 0.91 (s, 9 H), 2.02 (m, 1 H), 2.18 (m, 1 H), 2.42 (dd, J=13.42, 11.58 Hz, 1 H), 3.11 (m, 7 H), 3.42 (dd, J=14.71, 3.31 Hz, 1 H), 3.72 (m, 1 H), 3.98 (s, 1 H), 4.05 (m, 1 H), 4.42 (d, J=14.71 Hz, 1 H), 4.53 (m, J=13.24 ' Hz, 2 H), 7.06 (m, 6 H), 7.31 (s, 1 H), 7.54 (d, J=5.15 Hz, 1 H), 7.60 (d, J=3.68 Hz, 1 H), 7.77 (d, J=8.82 Hz, 2 H), 7.85 (d, J=8.82 Hz, 2 H), 8.14 (s, 1 H) Example 250 Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.62 Hz, 3 H), 0.85 (t, J=7.35 Hz, 6 H), 0.90 (d, J=6.62 Hz, 3 H), 1.35 (m, 3 H), 1.85 (m, 1 H), 2.00 (m, 1 H), 2.55 (s, 3 H), 2.99 (m, 9 H), 3.79 (m, J=11.03 Hz, 2 H), 4.20 (m, J=4.78 Hz, 1 H), 4.26 (d, J=15.44 Hz, 1 H), 4.42 (d, J=15.08 Hz, 1 H), 6.49 (d, J=8.82 Hz, 1 H), 7.17 (m, 6 H), 7.45 (dd, J=7.72, 1.47 Hz, 1 H), 7.71 (d, J=8.46 Hz, 2 H), 7.79 (d, J=8.46 Hz, 2 H), 8.16 (s, 1 H), 8.43 (dd, J=4.96, 1.65 Hz, 1 H) Example 251 Η NMR (300 MHz, CDC13) δ ppm 0.73 (d, J=6.62 Hz, 3 H), 0.84 (dd, J=15.44, 6.99 Hz, 6 H), 0.91 (d, J=6.62 Hz, 3 H), 0.99 (m, 1 H), 1.27 (m, 1 H), 1.85 (m, J=7.72 Hz, 2 H), 2.55 (s, 3 H), 2.96 (m, 10 H), 3.76 (m, 2 H), 4.19 (m, J=15.08 Hz, 2 H), 4.41 (d, J=15.08 Hz, 1 H), 6.45 (d, J=8.82 Hz, 1 H), 7.18 (m, 5 H), 7.49 (dd, J=7.91, 2.39 Hz, 1 H), 7.72 (d, J=8.82 Hz, 2 H), 7.80 (d, J=8.46 Hz, 2 H), 8.16 (s, 1 H), 8.17 (s, 1 H), 8.40 (d, J=2.57 Hz, 1 H) Example 252
Η NMR (300 MHz, CD3OD) δ ppm 0.73 (d, J=6.62 Hz, 3 H), 0.86 (dd, J=9.74, 6.80 Hz, 9 H), 0.91 (d, J=6.62 Hz, 4 H), 0.99 (m, 1 H), 1.16 (s, 1 H), 1.34 (m, 2 H), 1.87 (d, J=10.66 Hz, 1 H), 2.03 (m, 1 H), 2.50 (dd, J=13.60, 11.40 Hz, 1 H), 2.63 (m, 1 H), 2.97 (s, 3 H), 3.12 (m, 4 H), 3.44 (dd, J=14.71, 3.68 Hz, 1 H), 3.75 (m, 1 H), 3.83 (d, J=11.40 Hz, 1 H), 4.12 (m, 2 H), 4.35 (d, J=15.81 Hz, 1 H), 4.57 (m, 3 H), 4.77 (d, J=9.93 Hz, 2 H), 7.09 (m, 3 H), 7.17 (m, 2 H), 7.22 (d, J=7.72 Hz, 1 H), 7.78 (m, 4 H), 7.83 (d, J=8.82 Hz, 2 H), 8.14 (s, 1 H) Example 253 Η NMR (300 MHz, CD3OD) δ ppm 0.87 (m, 6 H), 0.92 (s, 9 H), 2.02 (m, 1 H), 2.29 (q, J=9.19 Hz, 1 H), 2.45 (dd, J=13.60, 11.40 Hz, 1 H), 3.11 (m, 9 H), 3.43 (dd, J=14.71, 3.31 Hz, 1 H), 3.73 (m, 1 H), 3.99 (s, 1 H), 4.07 (m, 1 H), 4.39 (d, J=15.81 Hz, 1 H), 4.56 (d, J=15.44 Hz, 1 H), 4.70 (s, 2 H), 7.12 (m, 5 H), 7.22 (d, J=7.72 Hz, 1 H), 7.45 (d, J=8.09 Hz, 1 H), 7.81 (m, 5 H), 8.14 (s, I H) Example 254 Η NMR (300 MHz, CD3OD) δ ppm 0.72 (d, J=6.25 Hz, 3 H), 0.85 (dd, J=15.08, 6.99 Hz, 6 H), 0.91 (d, J=6.62 Hz, 3 H), 1.00 (m, 1 H), 1.32 (m, 1 H), 1.85 (m, 1 H), 2.03 (m, 1 H), 2.51 (m, 2 H), 3.09 (m, 8 H), 3.44 (dd, J=14.71, 3.31 Hz, 1 H), 3.75 (m, 1 H), 3.85 (d, J=11.03 Hz, 1 H), 4.11 (dd, J=10.11, 7.91 Hz, 1 H), 4.36 (d, J=15.44 Hz, 1 H), 4.54 (d, J=15.08 Hz, 1 H), 7.04 (m, 3 H), 7.14 (m, 2 H), 7.42 (d, J=7.72 Hz, 1 H), 7.50 (t, J=7.91 Hz, 1 H), 7.61 (d, J=3.31 Hz, 1 H), 7.78 (d, J=8.82 Hz, 2 H), 7.84 (d, J=8.46 Hz, 2 H), 7.88 (m, 2 H), 7.98 (d, J=9.56 Hz, I H), 8.14 (s, 1 H) Example 255
Η NMR (300 MHz, CD3OD) δ ppm 0.72 (d, J=6.62 Hz, 3 H), 0.82 (t, J=7.35 Hz, 3 H), 0.87 (d, J=6.99 Hz, 3 H), 0.91 (d, J=6.62 Hz, 3 H), 0.99 (m, 1 H), 1.33 (m, 1 H), 1.85 (s, 1 H), 2.01 (m, 1 H), 2.47 (dd, J=13.79, 11.21 Hz, 1 H), 2.57 (m, 1 H), 3.06 (m, 8 H), 3.45 (dd, J=14.71, 3.31 Hz, 1 H), 3.75 (m, 1 H), 3.85 (d, J=11.40 Hz, 1 H), 4.11 (m, 1 H), 4.40 (d, J=15.08 Hz, 1 H), 4.57 (d, J=15.08 Hz, 1 H), 7.03 (dd, J=6.43, 3.86 Hz, 3 H), 7.14 (m, 2 H), 7.47 (d, J=7.72 Hz, 1 H), 7.56 (m, 2 H), 7.77 (d, J=8.46 Hz, 2 H), 7.83 (d, J=8.82 Hz, 2 H), 7.88 (m, 1 H), 7.98 (m, 2 H), 8.11 (m, 1 H), 8.14 (s, 1 H), 8.67 (d, J=4.41 Hz, 1 H) Example 256
Η NMR (300 MHz, CD3OD) δ ppm 0.88 (d, J=7.72 Hz, 6 H), 0.91 (s, 9 H), 2.00 (d, J=6.25 Hz, 1 H), 2.22 (q, J=9.07 Hz, 1 H), 2.43 (m, 1 H), 2.50 (s, 3 H), 3.10 (m, 10 H), 3.42 (dd, J=14.71, 3.31 Hz, 1 H), 3.72 (m, 1 H), 3.98 (s, 1 H), 4.06 (d, J=10.66 Hz, 1 H), 4.54 (t, J=15.08 Hz, 2 H), 7.06 (m, 5 H), 7.54 (s, 1 H), 7.77 (d, J=8.46 Hz, 1 H), 7.83 (d, J=8.46 Hz, 1 H), 7.96 (d, J=9.19 Hz, 1 H), 8.14 (s, 1 H) Example 257 Η NMR (300 MHz, CDC13) δ ppm 0.87 (d, J=6.62 Hz, 3 H), 0.90 (d, J=6.62 Hz, 3 H), 0.95 (s, 9 H), 1.88 ( , 1 H), 2.93 (m, 8 H), 3.34 (m, 1 H), 3.83 (m, 1 H), 3.89 (s, 3 H), 3.94 (d, J=3.31 Hz, 1 H), 4.00 (s, 1 H), 4.15 (m, 1 H), 4.63 (d, J=15.44 Hz, 1 H), 4.83 (d, J=15.44 Hz, 1 H), 6.21 (d, J=8.82 Hz, 1 H), 7.09 (m, 5 H), 7.25 (m, 1 H), 7.71 (d, J=8.82 Hz, 2 H), 7.79 (d, J=8.46 Hz, 2 H), 8.03 (m, 1 H), 8.18 (s, 1 H), 8.40 (dd, J=4.78, 1.47 Hz, 1 H) Example 258
Η NMR (300 MHz, CDC13) δ ppm 0.73 (t, J=5.52 Hz, 3 H), 0.84 (dd, J=12.50, 6.99 Hz, 6 H), 0.90 (d, J=6.25 Hz, 3 H), 0.97 (m, 1 H), 1.33 (m, 1 H), 1.85 (m, 1 H), 1.97 (m, J=8.82 Hz, 1 H), 2.34 (s, 3 H), 2.59 (s, 3 H), 2.97 (m, 8 H), 3.79 (m, 3 H), 4.20 (m, 1 H), 4.39 (d, J=14.71 Hz, 1 H), 4.48 (d, J=14.71 Hz, 1 H), 6.52 (d, J=8.46 Hz, 1 H), 6.97 (d, J=5.15 Hz, 1 H), 7.20 (m, 5 H), 7.70 (d, J=8.46 Hz, 2 H), 7.79 (d, J=8.82 Hz, 2 H), 8.16 (s, 1 H), 8.30 (d, J=5.15 Hz, 2 H) Example 259
Η NMR (300 MHz, CD3OD) δ ppm 0.72 (d, J=6.62 Hz, 3 H), 0.85 (m, 6 H), 0.91 (d, J=6.62 Hz, 3 H), 1.00 (m, 1 H), 1.32 (m, 1 H), 1.86 (m, 1 H), 2.02 (m, 1 H), 2.47 (m, 3 H), 3.08 (m, 7 H), 3.44 (dd, J=14.89, 3.49 Hz, 1 H), 3.75 (m, 1 H), 3.85 (d, J=l 1.03 Hz, 1 H), 4.11 (m, 1 H), 4.30 (d, J=14.71 Hz, 1 H), 4.48 (d, J=14.71 Hz, 1 H), 6.79 (d, J=1.84 Hz, 1 H), 7.04 (m, 3 H), 7.13 (m, 2 H), 7.19 (d, J=7.72 Hz, 1 H), 7.37 (m, 1 H), 7.49 (m, 1 H), 7.55 (m, 1 H), 7.78 (d, J=8.46 Hz, 2 H), 7.84 (d, J=8.82 Hz, 2 H), 7.88 (m, 1 H), 7.96 (d, J=9.56 Hz, 1 H), 8.14 (s, l H) Example 260
Η NMR (300 MHz, CD3OD) δ ppm 0.72 (d, J=6.62 Hz, 3 H), 0.82 (t, J=7.35 Hz, 3 H), 0.88 (d, J=6.62 Hz, 3 H), 0.91 (d, J=6.62 Hz, 3 H), 1.00 (m, 2 H), 1.31 (m, 1 H), 1.86 (m, 1 H), 2.00 (m, 1 H), 2.51 (m, 2 H), 3.07 (m, 8 H), 3.75 (m, 1 H), 3.85 (d, J=11.03 Hz, 1 H), 4.11 (m, 1 H), 4.39 (d, J=15.08 Hz, 1 H), 4.57 (d, J=15.08 Hz, 1 H), 7.04 (m, 3 H), 7.13 (m, 2 H), 7.44 (d, J=7.72 Hz, 1 H), 7.56 (t, J=7.54 Hz, 1 H), 7.66 (m, 2 H), 7.77 (d, J=8.46 Hz, 2 H), 7.83 (d, J=8.46 Hz, 2 H), 7.97 (d, J=9.93 Hz, 1 H), 8.14 (s, 1 H), 9.06 (s, 1 H), 9.14 (s, 1 H) Example 261
Η NMR (300 MHz, CD3OD) δ ppm 0.71 (d, J=6.62 Hz, 3 H), 0.85 (dd, J=16.18, 6.99 Hz, 6 H), 0.91 (d, J=6.62 Hz, 3 H), 0.97 (m, 1 H), 1.28 (m, 1 H), 1.83 (s, 1 H), 2.01 (m, 1 H), 2.51 (m, 2 H), 3.08 (m, 8 H), 3.44 (m, 1 H), 3.74 (m, 1 H), 3.84 (m, 1 H), 3.90 (s, 3 H), 4.12 (m, 1 H), 4.24 (m, 1 H), 4.39 (d, J=15.08 Hz, 1 H), 6.81 (d, J=8.46 Hz, 1 H), 7.06 (m, 3 H), 7.15 (m, 2 H), 7.63 (dd, J=8.64, 2.39 Hz, 1 H), 7.78 (m, 2 H), 7.84 (d, J=8.82 Hz, 2 H), 8.08 (d, J=1.84 Hz, I H), 8.14 (s, I H) Example 262
Η NMR (300 MHz, CD3OD) δ ppm 0.87 (m, 6 H), 0.92 (s, 9 H), 2.03 (d, J=6.25 Hz, 1 H), 2.22 (t, J=8.46 Hz, 1 H), 2.43 (m, 1 H), 3.09 (m, 9 H), 3.42 (m, 1 H), 3.74 (m, 1 H), 4.00 (s, 1 H), 4.05 (m, 1 H), 4.58 (s, 2 H), 7.08 (m, 5 H), 7.60 (s, 1 H), 7.77 (d, J=8.46 Hz, 2 H), 7.84 (d, J=6.62 Hz, 2 H), 8.14 (s, 1 H), 8.62 (d, J=2.57 Hz, 1 H), 9.37 (s, 1 H) Example 263 Η NMR (300 MHz, CD3OD) δ ppm 0.88 (d, J=7.72 Hz, 6 H), 0.92 (s, 9 H), 1.53 (d, J=4.04 Hz, 6 H), 2.00 (m, 1 H), 2.24 (m, 1 H), 2.44 (dd, J=13.60, 11.77 Hz, 1 H), 3.12 (m, 10 H),
3.42 (dd, J=14.71, 3.31 Hz, 1 H), 3.73 (m, 1 H), 3.98 (s, 1 H), 4.08 (m, 1 H), 4.38 (d, J=15.44 Hz, 1 H), 4.62 (d, J=15.44 Hz, 1 H), 7.11 (m, 5 H), 7.53 (d, J=8.09 Hz, 1 H), 7.77 (m, 3 H), 7.84 (d, J=8.46 Hz, 2 H), 8.14 (s, 1 H) Example 264 Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.62 Hz, 3 H), 0.85 (t, J=7.35 Hz, 3 H), 1.00 (d, J=22.43 Hz, 2 H), 1.26 (s, 4 H), 1.58 (s, 8 H), 1.99 (s, 1 H), 2.11 (m, 1 H), 2.98 (m, 8 H), 3.81 (m, 3 H), 4.24 (m, 2 H), 4.43 (d, J=15.44 Hz, 1 H), 6.52 (d, J=8.82 Hz, 1 H), 7.17 (m, 5 H), 7.45 (d, J=6.62 Hz, 1 H), 7.70 (d, J=8.46 Hz, 2 H), 7.78 (d, J=8.46 Hz, 2 H), 8.16 (s, 1 H), 8.25 (s, 1 H), 8.43 (d, J=3.68 Hz, 1 H) Example 265
Η NMR (300 MHz, CDC13) δ ppm 0.88 (d, J=6.62 Hz, 3 H), 0.92 (d, J=6.62 Hz, 3 H), 0.96 (s, 9 H), 1.85 (dd, J=14.34, 6.99 Hz, 1 H), 2.56 (s, 3 H), 2.69 (dd, J=13.97, 10.30 Hz, 1 H), 3.02 (m, 7 H), 3.31 (m, 1 H), 3.77 (d, J=3.68 Hz, 2 H), 4.00 (s, 1 H), 4.20 (m, 2 H), 4.42 (d, J=14.71 Hz, 1 H), 6.18 (d, J=9.19 Hz, 1 H), 7.14 (m, 5 H), 7.51 (dd, J=7.72, 2.21 Hz, 1 H), 7.72 (d, J=8.46 Hz, 2 H), 7.80 (d, J=8.46 Hz, 2 H), 7.87 (m, 1 H), 8.17 (s, 1 H), 8.42 (m, 1 H) Example 266
Η NMR (300 MHz, CDC13) δ ppm 0.89 (t, J=6.62 Hz, 6 H), 0.98 (m, 9 H), 1.88 (m, 1 H), 2.95 (m, 8 H), 3.41 (m, 1 H), 3.88 (m, 2 H), 4.04 (d, J=3.31 Hz, 1 H), 4.29 (m, 2 H), 4.51 (d, J=16.18 Hz, 1 H), 6.42 (d, J=9.19 Hz, 1 H), 7.15 (m, 5 H), 7.36 (dd, J=5.15, 2.57 Hz, 1 H), 7.70 (d, J=8.46 Hz, 2 H), 7.80 (m, 2 H), 8.16 (s, 1 H), 9.15 (m, 2 H) Example 267
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.62 Hz, 3 H), 0.88 (m, 9 H), 1.00 (m, 1 H), 1.35 (m, 1 H), 1.86 (m, 1 H), 1.98 (m, 1 H), 2.77 (dd, J=14.34, 10.30 Hz, 1 H), 2.88 (dd, J=13.60, 6.99 Hz, 1 H), 3.09 (m, 7 H), 3.82 (m, 3 H), 4.23 (m, 2 H), 4.50 (d, J=16.18 Hz, 1 H), 6.54 (d, J=8.82 Hz, 1 H), 7.18 (m, 5 H), 7.34 (dd, J=5.15, 2.21 Hz, 1 H), 7.70 (d, J=8.82 Hz, 2 H), 7.79 (d, J=8.46 Hz, 2 H), 8.16 (s, 1 H), 9.15 (m, 2 H) Example 268 Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.62 Hz, 3 H), 0.84 (m, 6 H), 0.89 (d, J=6.62 Hz, 3 H), 0.98 (m, 1 H), 1.33 (m, 1 H), 1.86 (m, 1 H), 1.98 (m, 1 H), 2.76 (dd, J=14.34, 10.30 Hz, 1 H), 2.88 (m, 2 H), 2.98 (m, 1 H), 3.17 (m, 6 H), 3.84 (m, 1 H), 3.93 (t, J=3.86 Hz, 1 H), 4.21 (m, 1 H), 4.59 (d, J=15.44 Hz, 1 H), 4.75 (d, J=15.81 Hz, 1 H), 6.54 (d, J=8.82 Hz, 1 H), 7.18 (m, 5 H), 7.49 (m, 2 H), 7.70 (d, J=8.46 Hz, 2 H), 7.79 (d, J=8.46 Hz, 2 H), 8.16 (s, 1 H), 8.34 (s, l H) Example 269
Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.25 Hz, 3 H), 0.84 (m, 6 H), 0.90 (d, J=6.62 Hz, 3 H), 0.97 (m, 1 H), 1.29 (m, 1 H), 1.93 (m, 2 H), 2.76 (dd, J=14.52, 10.48 Hz, 1 H), 3.05 (m, 8 H), 3.77 (d, J=11.03 Hz, 1 H), 3.87 (s, 3 H), 3.87 (m, 2 H), 4.14 (m, 1 H), 4.58 (d, J=15.08 Hz, 1 H), 4.85 (d, J=15.44 Hz, 1 H), 6.44 (d, J=8.46 Hz, 1 H), 7.14 (m, 5 H), 7.25 (dd, J=8.09, 4.78 Hz, 1 H), 7.70 (d, J=8.46 Hz, 2 H), 7.79 (d, J=8.46 Hz, 2 H), 8.01 (dd, J=8.09, 1.47 Hz, 1 H), 8.18 (s, 1 H), 8.40 (dd, J=4.78, 1.47 Hz, 1 H) Example 270 Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.78 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.86 (s, 1 H), 2.13 (d, J=21.02 Hz, 1 H), 2.93 (td, J=8.82, 7.12 Hz, 2 H), 3.14 (m, 9 H), 3.63 (d, J=10.51 Hz, 1 H), 3.78 (s, 1 H), 4.15 (s, 1 H), 4.40 (d, J=14.92 Hz, 1 H), 4.48 (d, J=15.26 Hz, 1 H), 6.52 (d, J=8.14 Hz, 1 H), 6.96 (s, 1 H), 7.19 (m, 5 H), 7.70 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H) Example 273
Η NMR (300 MHz, CD3OD) δ ppm 0.78 (d, J=6.44 Hz, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.40 (m, 1 H), 2.04 (m, 2 H), 2.52 (dd, J=13.90, 11.53 Hz, 1 H), 2.67 (m, 1 H), 2.81 (s, 3 H), 3.09 (m, 4 H), 3.47 (dd, J=14.92, 3.73 Hz, 1 H), 3.75 (m, 2 H), 4.14 (m, 1 H), 4.37 (d, J=15.60 Hz, 1 H), 4.55 (s, 2 H), 4.64 (d, J=15.60 Hz, 1 H), 4.80 (s, 1 H), 7.15 (m, 5 H), 7.51 (s, 1 H), 7.77 (d, J=8.48 Hz, 2 H), 7.83 (d, J=8.48 Hz, 2 H), 7.95 (d, J=9.83 Hz, 1 H), 8.14 (s, I H) Example 274
Η NMR (300 MHz, CD3OD) δ ppm 0.78 (m, 6 H), 1.73 (s, 1 H), 2.15 (m, 4 H), 2.54 (m, 2 H), 2.69 (s, 3 H), 2.81 (dd, J=14.58, 8.82 Hz, 1 H), 2.97 (d, J=14.92 Hz, 1 H), 3.17 (m, 4 H), 3.40 (m, 2 H), 3.68 (m, 4 H), 3.88 (m, 1 H), 4.11 (s, 2 H), 4.42 (s, 2 H), 7.13 (m, 5 H), 7.20 (s, 1 H), 7.83 (d, J=8.82 Hz, 2 H), 7.88 (m, 2 H), 8.04 (m, 1 H), 8.16 (s, 1 H) Example 275
Η NMR (300 MHz, CDC13) δ ppm 0.66 (d, J=6.78 Hz, 3 H) 0.74 (d, J=6.78 Hz, 3 H) 0.86 (t, J=6.44 Hz, 6 H) 1.88 (dd, J=13.73, 6.95 Hz, 1 H) 2.29 (m, 1 H) 2.68 (s, 3 H) 2.79 (dd, J=14.07, 10.00 Hz, 1 H) 2.94 (t, J=6.78 Hz, 1 H) 3.08 (dd, J=14.07, 4.92 Hz, 1 H) 3.17 (m, 2 H) 3.90 (m, 1 H) 4.03 (d, J=10.51 Hz, 1 H) 4.18 (m, 1 H) 4.88 (s, 2 H) 6.22 (d, J=3.05 Hz, 1 H) 6.33 (d, J=2.71 Hz, 1 H) 6.94 (s, 1 H) 7.08 (m, 3 H) 7.43 (m, 2 H) 7.61 (m, 1 H) 7.66 (d, J=8.48 Hz, 2 H) 7.78 (m, 2 H) 7.83 (d, J=7.46 Hz, 1 H) 8.13 (s, 1 H) Example 276
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.83 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 1.86 (m, 1 H), 2.16 (m, 1 H), 2.97 (m, 10 H), 3.66 (d, J=10.85 Hz, 1 H), 3.82 (d, J=5.43 Hz, 1 H), 4.18 (d, J=14.92 Hz, 2 H), 4.31 (d, J=14.92 Hz, 1 H), 6.63 (m, 5 H), 7.16 (m, 5 H), 7.70 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.15 (s, I H) Example 277 Η NMR (300 MHz, CD3OD) δ ppm 0.72 (d, J=6.78 Hz, 3 H), 0.84 (m, 6 H), 0.88 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 0.97 (dd, J=8.14, 5.76 Hz, 1 H), 1.30 (m, 1 H), 1.85 (s, 1 H), 2.03 (d, J=7.12 Hz, 1 H), 2.51 (dd, J=13.90, 11.53 Hz, 1 H), 2.67 (m, 1 H), 3.09 (m, 5 H), 3.45 (dd, J=14.75, 3.56 Hz, 1 H), 3.75 (m, 1 H), 3.82 (d, J=11.19 Hz, 1 H), 4.13 (s, 1 H), 4.28 (d, J=15.94 Hz, 1 H), 4.52 (d, J=15.60 Hz, 1 H), 7.12 (m, 3 H), 7.17 (m, 2 H), 7.56 (m, 1 H), 7.78 (d, J=8.82 Hz, 2 H), 7.84 (d, J=8.48 Hz, 2 H),'7.97 (m, 1 H), 8.14 (s, 1 H), 8.28 (m, 1 H), 8.31 (s, I H) Example 278
Η NMR (300 MHz, CD3OD) δ ppm 0.73 (d, J=6.44 Hz, 3 H), 0.86 (m, 6 H), 0.91 (d, J=6.44 Hz, 3 H), 1.00 (m, 1 H), 1.33 (m, 1 H), 1.87 (s, 1 H), 2.03 (m, 1 H), 2.53 (dd, J=13.90, 11.19 Hz, 1 H), 2.76 (m, 1 H), 3.09 (m, 8 H), 3.46 (dd, J=14.92, 3.39 Hz, 1 H), 3.76 (m, 1 H), 3.82 (d, J=11.19 Hz, 1 H), 4.11 (d, J=6.78 Hz, 1 H), 4.28 (d, J=16.62 Hz, 1 H), 4.55 (d, J=l6.28 Hz, 1 H), 7.16 (m, 5 H), 7.45 (d, J=7.12 Hz, 1 H), 7.78 (d, J=8.48 Hz, 2 H), 7.84 (d, J=8.48 Hz, 2 H), 7.97 (m, 1 H), 8.14 (s, 1 H), 8.31 (d, J=7.12 Hz, 2 H) Example 279 Η NMR (300 MHz, CD3OD) δ ppm 0.73 (d, J=6.78 Hz, 3 H), 0.85 (m, 6 H), 0.91 (d, J=6.44 Hz, 3 H), 0.97 (d, J=9.16 Hz, 1 H), 1.32 (m, 1 H), 1.84 (s, 1 H), 1.99 (d, J=14.58 Hz, 1 H), 2.52 (dd, J=14.07, 11.36 Hz, 1 H), 2.72 (m, 1 H), 3.10 (m, 9 H), 3.47 (dd, J=14.92, 3.73 Hz, 1 H), 3.76 (m, 1 H), 3.82 (d, J=11.19 Hz, 1 H), 4.14 (d, J=10.85 Hz, 1 H), 4.36 (d, J=15.60 Hz, 1 H), 4.47 (s, 2 H), 4.63 (d, J=15.94 Hz, 1 H), 7.15 (m, 5 H), 7.47 (s, 1 H), 7.78 (d, J=8.82 Hz, 2 H), 7.83 (d, J=8.48 Hz, 2 H), 7.94 (d, J=9.49 Hz, 1 H), 8.14 (s, 1 H) Example 280
Η NMR (300 MHz, CD3OD) δ ppm 0.75 (d, J=6.78 Hz, 3 H), 0.85 (t, J=7.12 Hz, 3 H), 0.97 (m, 1 H), 1.29 (s, 1 H), 1.67 (m, J=18.65 Hz, 1 H), 1.81 (dd, J=10.34, 6.61 Hz, 4 H), 2.02 (d, J=10.85 Hz, 2 H), 2.52 ( , 1 H), 2.61 (m, 1 H), 2.71 (d, J=7.80 Hz, 1 H), 3.11 (m, 6 H), 3.36 (m, 1 H), 3.45 (m, 1 H), 3.75 (d, J=6.44 Hz, 1 H), 3.84 (d, J=10.85 Hz, 1 H), 4.14 (s, 1 H), 4.36 (d, J=15.26 Hz, 1 H), 4.47 (s, 2 H), 4.63 (d, J=15.94 Hz, 1 H), 7.16 (m, 5 H), 7.47 (s, 1 H), 7.78 (d, J=8.48 Hz, 2 H), 7.83 (d, J=8.48 Hz, 2 H), 7.94 (d, J=9.16 Hz, 1 H), 8.15 (s, 1 H) Example 281
Η NMR (300 MHz, CD3OD) δ ppm 0.75 (d, J=6.44 Hz, 3 H), 0.84 (t, J=7.29 Hz, 3 H), 0.97 (m, 1 H), 1.17 (m, 1 H), 1.32 (m, 3 H), 1.58 (m, 6 H), 1.85 (s, 1 H), 2.26 (m, 1 H), 2.53 (dd, J=13.73, 11.36 Hz, 1 H), 2.70 (m, 1 H), 3.14 (m, 6 H), 3.48 (dd, J=14.92, 4.07 Hz, 1 H), 3.78 (dd, J=11.19, 4.75 Hz, 1 H), 3.83 (d, J=11.19 Hz, 1 H), 4.15 (s, 1 H), 4.36 (d, J=15.60 Hz, 1 H), 4.47 (s, 2 H), 4.63 (d, J=15.94 Hz, 1 H), 7.16 (m, 5 H), 7.47 (s, 1 H), 7.78 (d, J=8.82 Hz, 2 H), 7.84 (d, J=8.48 Hz, 2 H), 7.94 (d, J=9.49 Hz, 1 H), 8.14 (s, 1 H) Example 282 Η NMR (300 MHz, CD3OD) δ ppm 0.79 (m, 6 H) 0.87 (d, J=6.78 Hz, 3 H) 0.91 (d, J=6.78 Hz, 3 H) 0.97 (m, 1 H) 1.16 (m, 1 H) 1.98 (m, 2 H) 2.24 (s, 3 H) 2.56 (dd, J=13.90, 10.85 Hz, 1 H) 2.98 (m, 1 H) 3.10 (m, 3 H) 3.43 (dd, J=14.92, 2.37 Hz, 1 H) 3.77 (m, 1 H) 4.05 (m, 1 H) 4.16 (d, J=10.85 Hz, 1 H) 4.81 (m, J=9.49 Hz, 2 H) 4.86 (m, 1 H) 4.95 (m, 1 H) 6.38 (m, 1 H) 6.42 (d, J=3.05 Hz, 1 H) 6.99 (m, 3 H) 7.07 (m, 2 H) 7.19 (dd, J=5.09, 1.70 Hz, 1 H) 7.76 (s, 1 H) 7.79 (m, 1 H) 7.86 (d, J=8.82 Hz, 2 H) 8.17 (d, J=8.48 Hz, 2 H) 8.48 (d, J=5.09 Hz, 1 H)
Example 283
Η NMR (300 MHz, CD3OD) δ ppm 0.73 (d, J=6.78 Hz, 3 H), 0.84 (t, J=7.29 Hz, 3 H), 0.95 (d, J=16.28 Hz, 1 H), 1.08 (d, J=6.10 Hz, 6 H), 1.31 (m, 3 H), 1.59 (d, J=16.95 Hz, 6 H), 1.89 (s, 1 H), 2.27 (m, 1 H), 2.48 (m, 1 H), 2.57 (m, 1 H), 2.86 (m, 1 H), 3.13 (m, 9 H), 3.46 (dd, =14.75, 3.90 Hz, 1 H), 3.77 (m, 1 H), 3.82 (d, J=11.19 Hz, 1 H), 4.07 (s, 2 H), 4.11 (m, 1 H), 4.44 (m, 2 H), 7.12 (m, 5 H), 7.30 (s, 1 H), 7.77 (d, J=8.48 Hz, 2 H), 7.83 (d, J=8.48 Hz, 2 H), 8.14 (s, l H) Example 284 Η NMR (300 MHz, CD3OD) δ ppm 0.55 (m, 2 H), 0.63 (m, 3 H), 0.71 (d, J=6.44 Hz, 3 H), 1.08 (d, J=6.44 Hz, 6 H), 1.22 (s, 3 H), 1.61 (m, 6 H), 2.29 (m, 1 H), 2.52 (dd, J=14.24, 11.53 Hz, 1 H), 2.84 (m, 1 H), 3.20 (m, 9 H), 3.44 (m, 1 H), 3.60 (m, 1 H), 3.79 (d, J=11.19 Hz, 1 H), 4.01 (s, 2 H), 4.10 (m, 1 H), 4.28 (d, J=15.94 Hz, 1 H), 4.42 (d, J=15.94 Hz, 1 H), 7.17 (m, 5 H), 7.24 (s, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.81 (d, J=8.82 Hz, 2 H), 8.13 (s, 1 H) Example 285 Η NMR (300 MHz, CD3OD) δ ppm 0.72 (d, J=6.44 Hz, 3 H), 0.86 (dd, J=12.72, 6.95 Hz, 6 H), 0.91 (d, J=6.44 Hz, 3 H), 0.99 (m, 1 H), 1.32 (m, 1 H), 1.85 (m, 1 H), 2.02 (m, 1 H), 2.51 (m, 2 H), 3.07 (m, 9 H), 3.44 (dd, J=14.92, 3.39 Hz, 1 H), 3.75 (m, 1 H), 3.83 (d, J=11.19 Hz, 1 H), 4.13 (m, 1 H), 4.29 (d, J=14.92 Hz, 1 H), 4.49 (d, J=14.92 Hz, 1 H), 7.06 (m, 3 H), 7.15 (m, 2 H), 7.38 (t, J=3.05 Hz, 1 H), 7.38 (m, 2 H), 7.59 (m, 2 H), 7.78 (d, J=8.82 Hz, 2 H), 7.84 (d, J=8.82 Hz, 2 H), 7.89 (s, 1 H), 8.14 (s, 1 H) Example 286 Η NMR (300 MHz, CDC13) δ ppm 0.73 (d, J=6.78 Hz, 3 H), 0.85 (dd, J=8.99, 6.95 Hz, 6 H), 0.91 (t, J=5.76 Hz, 3 H), 1.00 (m, 1 H), 1.26 (s, 1 H), 1.38 (m, 1 H), 1.53 (s, 1 H), 1.87 (m, 1 H), 1.98 (m, 1 H), 2.87 (m, 3 H), 3.15 (m, 5 H), 3.82 (m, 3 H), 4.17 (m, 1 H), 4.37 (d, J=15.60 Hz, 1 H), 4.59 (d, J=15.60 Hz, 1 H), 4.74 (d, J=4.75 Hz, 2 H), 6.53 (d, J=8.82 Hz, 1 H), 7.17 (m, 6 H), 7.66 (m, 1 H), 7.70 (d, J=6.78 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 7.97 (s, 1 H), 8.15 (s, 1 H) Example 287
Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.78 Hz, 3 H), 0.85 (t, J=6.27 Hz, 6 H), 0.90 (d, J=6.44 Hz, 3 H), 1.03 (dd, J=12.55, 9.16 Hz, 1 H), 1.52 (s, 1 H), 1.86 (s, 1 H), 1.99 (m, 1 H), 2.86 (m, 4 H), 3.14 (m, 5 H), 3.78 (m, J=10.85 Hz, 2 H), 3.88 (d, J=3.73 Hz, 1 H), 4.12 (d, J=7.12 Hz, 1 H), 4.16 (s, 1 H), 4.41 (d, J=15.94 Hz, 1 H), 4.58 (d, J=15.60 Hz, 1 H), 6.53 (m, 1 H), 7.19 (m, 6 H), 7.66 (m, 3 H), 7.79 (d, J=8.82 Hz, 2 H), 8.15 (s, 1 H), 8.20 (s, 1 H) Example 288 Η NMR (300 MHz, CD3OD) δ ppm 0.88 (d, J=6.99 Hz, 6 H), 0.92 (s, 9 H), 1.47 (dd, J=6.62, 1.84 Hz, 3 H), 2.02 (m, 1 H), 2.29 (m, 1 H), 2.45 (t, J=12.13 Hz, 1 H), 3.09 (m, 10 H), 3.43 (dd, J=15.08, 3.31 Hz, 1 H), 3.73 (m, 1 H), 3.99 (s, 1 H), 4.07 (m, 1 H), 4.38 (d, J=15.44 Hz, 1 H), 4.59 (d, J=15.44 Hz, 1 H), 7.15 (m, 5 H), 7.45 (dd, J=7.72, 2.21 Hz, 1 H), 7.81 (m, 6 H), 8.14 (s, I H) Example 363 Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.83 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.83 (d, J=6.44 Hz, 1 H), 2.09 (m, 1 H), 2.68 (dd, J=14.24, 10.85 Hz, 1 H), 2.84 (dd, J=13.56, 6.44 Hz, 1 H), 3.02 (m, 4 H), 3.21 (m, 1 H), 3.32 (d, J=17.97 Hz, 1 H), 3.61 (d, J=17.97 Hz, 1 H), 3.87 (m, J=10.85 Hz, 2 H), 4.25 (m, 1 H), 4.70 (t, J=14.92 Hz, 2 H), 6.08 (d, J=9.16 Hz, 1 H), 7.09 (m, 5 H), 7.53 (m, 1 H), 7.56 (d, J=2.37 Hz, 1 H), 7.72 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (dd, J=8.99, 1.53 Hz, 1 H), 8.17 (s, 1 H), 8.24 (d, J=2.03 Hz, 1 H) Example 364
Η NMR (300 MHz, CD3OD) δ ppm 0.79 (J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 2.02 (m, 2 H), 2.50 (dd, J=13.90, 11.53 Hz, 1 H), 2.95 (m, 1 H), 3.09 (m, 5 H), 3.21 (dd, J=13.90, 3.73 Hz, 1 H), 3.44 (dd, J=14.92, 3.39 Hz, 1 H), 3.78 (m, 2 H), 3.96 (s, 3 H), 4.02 (d, J=10.85 Hz, 1 H), 4.14 (m, 1 H), 4.95 (d, J=16.28 Hz, 1 H), 5.02 (d, J=16.28 Hz, 1 H), 7.01 (m, 3 H), 7.15 (m, 2 H), 7.27 (m, 2 H), 7.51 (d, J=7.80 Hz, 1 H), 7.59 (d, J=7.46 Hz, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.82 (d, J=8.82 Hz, 1 H), 8.13 (s, l H). Example 365
Η NMR (300 MHz, CDC13) δ ppm 0.82 (d, J=6.44 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.89 (d, J=3.39 Hz, 3 H), 0.92 (d, J=3.39 Hz, 3 H), 1.85 (d, J=7.12 Hz, 1 H), 2.16 (m, 1 H), 2.70 (dd, J=14.24, 10.51 Hz, 1 H), 2.84 (dd, J=13.56, 6.78 Hz, 1 H), 3.00 (m, 1 H), 3.07 (m, 2 H), 3.21 (m, 1 H), 3.45 (d, J=17.63 Hz, 1 H), 3.76 (m, 2 H), 3.84 (d, J=3.05 Hz, 1 H), 3.92 (d, J=10.85 Hz, 1 H), 4.25 (m, 1 H), 4.94 (d, J=15.94 Hz, 1 H), 5.03 (d, J=16.28 Hz, 1 H), 6.20 (d, J=9.16 Hz, 1 H), 7.16 (m, 5 H), 7.32 (d, J=8.48 Hz, 1 H), 7.49 (t, J=7.46 Hz, 1 H), 7.64 (m, 1 H), 7.72 (d, J=8.48 Hz, 2 H), 7.79 (m, 2 H), 7.82 (d, J=7.46 Hz, 1 H), 7.95 (d, J=8.82 Hz, 1 H), 8.12 (d, J=8.48 Hz, 1 H), 8.16 (s, 1 H). Example 366
Η NMR (300 MHz, DMSO-d6) δ ppm 0.68 (d, J=6.44 Hz, 3 H), 0.75 (d, J=6.78 Hz, 3 H), 0.82 (d, J=6.44 Hz, 6 H), 1.96 (m, 1 H), 2.37 (dd, J=13.05, 11.70 Hz, 1 H), 3.01 (m, 8 H), 3.59 (d, J=7.12 Hz, 1 H), 3.85 (m, 1 H), 3.91 (s, 3 H), 4.02 (d, J=10.85 Hz, 1 H), 5.01 (d, J=5.09 Hz, 2 H), 6.98 (m, 1 H), 7.12 (d, J=4.07 Hz, 5 H), 7.23 (dd, J=8.14, 4.75 Hz, 1 H), 7.77 (d, J=8.82 Hz, 2 H), 7.81 (d, J=8.82 Hz, 2 H), 7.89 (m, 1 H), 8.24 (s, 1 H), 8.33 (dd, J=4.75, 1.36 Hz, 1 H). Example 367 Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.78 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.83 (s, 1 H), 2.06 (m, 1 H), 2.65 (dd, J=14.24, 10.51 Hz, 1 H), 2.82 (m, 1 H), 3.04 (m, 3 H), 3.20 (m, 2 H), 3.54 (d, J=17.97 Hz, 1 H), 3.85 (d, J=11.19 Hz, 2 H), 4.22 (s, 1 H), 4.51 (d, J=2.37 Hz, 2 H), 5.92 (s, 2 H), 6.06 (d, J=9.49 Hz, 1 H), 6.75 (d, J=7.80 Hz, 1 H), 6.91 (m, 2 H), 7.07 (m, 5 H), 7.72 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H). Example 368
Η NMR (300 MHz, CDC13) δ ppm 0.88 (d, J=2.71 Hz, 3 H), 0.91 (d, J=3.05 Hz, 3 H), 1.86 (dd, J=14.07, 7.29 Hz, 1 H), 2.99 (m, 6 H), 3.45 (d, J=17.29 Hz, 1 H), 3.67 (m, 1 H), 3.73 (d, J=12.21 Hz, 1 H), 3.90 (m, 1 H), 3.98 (d, J=16.28 Hz, 1 H), 4.20 (s, 1 H), 4.63 (s, 2 H), 6.13 (d, J=8.82 Hz, 1 H), 7.13 (dd, J=6.78, 2.71 Hz, 2 H), 7.22 (m, 3 H), 7.31 (m, 2 H), 7.39 (m, 3 H), 7.73 (d, J=8.48 Hz, 2 H), 7.80 (m, 2 H), 8.16 (s, 1 H) Example 369
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.78 Hz, 3 H), 0.84 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.86 (s, 1 H), 2.09 (s, 1 H), 3.00 (m, 6 H), 3.49 (d, J=17.97 Hz, 1 H), 3.69 (d, J=17.97 Hz, 1 H), 3.92 (m, J=10.51 Hz, 2 H), 4.28 (s, 1 H), 4.71 (m, 2 H), 6.45 (d, J=7.80 Hz, 1 H), 7.14 (m, 5 H), 7.51 (m, 2 H), 7.70 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H), 8.66 (s, 2 H) Example 370 Η NMR (300 MHz, CD3OD) δ ppm 0.76 (d, J=3.73 Hz, 3 H), 0.79 (d, J=3.39 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.78 Hz, 3 H), 2.01 (m, 2 H), 2.40 (s, 6 H), 2.45 (m, 1 H), 3.03 (m, 4 H), 3.21 (dd, J=13.73, 3.56 Hz, 2 H), 3.45 (dd, J=14.75, 3.56 Hz, 1 H), 3.69 (d, J=17.97 Hz, 1 H), 3.76 (m, 1 H), 3.90 (s, 2 H), 4.00 (d, J=11.19 Hz, 1 H), 4.11 (m, 1 H), 4.75 (m, 2 H), 6.99 (m, 3 H), 7.12 ( , 2 H), 7.42 (s, 1 H), 7.78 (m, 2 H), 7.83 (d, J=8.82 Hz, 2 H), 8.14 (s, 1 H) Example 371
Η NMR (300 MHz, CDC13) δ ppm 0.80 (t, J=6.78 Hz, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.84 (dd, J=14.58, 6.78 Hz, 1 H), 2.09 (m, 1 H), 2.86 (dd, J=13.39, 6.95 Hz, 2 H), 3.12 (m, 8 H), 3.61 (d, J=17.63 Hz, 1 H), 3.83 (m, 1 H), 3.92 (d, J=10.85 Hz, 1 H),
4.23 (d, J=4.41 Hz, 1 H), 4.76 (m, 2 H), 6.37 (s, 1 H), 7.05 (s, 1 H), 7.13 (m, 5 H), 7.72 (d, J=8.48 Hz, 2 H), 7.80 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H)
Example 372 Η NMR (300 MHz, CD3OD) δ ppm 0.77 (d, J=4.07 Hz, 3 H), 0.80 (d, J=3.73 Hz, 3 H), 1.23 (d, J=28.82 Hz, 2 H), 1.63 (m, 6 H), 2.02 (m, 1 H), 2.27 (m, 1 H), 2.46 (m, 1 H), 2.65 (s, 3 H), 3.10 (m, 6 H), 3.47 (dd, J=14.75, 3.90 Hz, 1 H), 3.69 (d, J=17.97 Hz, 1 H), 3.79 (m, 1 H), 4.01 (d, J=11.19 Hz, 1 H), 4.16 (m, 1 H), 4.73 (m, 2 H), 6.98 (m, 3 H), 7.13 (dd, J=6.44, 3.05 Hz, 2 H), 7.24 (s, 1 H), 7.77 (d, J=8.82 Hz, 2 H), 7.83 (d, J=8.82 Hz, 2 H), 8.14 (s, 1 H) Example 373
Η NMR (300 MHz, CDC13) δ ppm 0.81 (dd, J=6.78, 3.05 Hz, 6 H), 0.86 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 1.87 (m, 1 H), 2.13 (m, J=10.17 Hz, 1 H), 2.93 (m, 5 H), 3.20 (m, 1 H), 3.47 (d, J=18.31 Hz, 1 H), 3.71 (d, J=17.97 Hz, 1 H), 3.85 (s, 1 H), 3.93 (d, J=10.51 Hz, 1 H), 4.27 (s, 1 H), 4.85 (d, J=1.70 Hz, 2 H), 6.38 (s, 1 H), 7.17 (m, 5 H), 7.26 (m, 2 H), 7.71 (m, J=8.48 Hz, 3 H), 7.80 (d, J=8.82 Hz, 2 H), 8.16 (s, 1 H), 8.55 (s, 1 H) Example 374
Η NMR (300 MHz, CDC13) δ ppm 0.83 (dd, J=6.27, 4.58 Hz, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 1.85 (m, 1 H), 2.13 (s, 1 H), 2.76 (m, 1 H), 2.84 (m, 1 H), 2.96 (s, 3 H), 3.01 (m, 2H), 3.20 (m, 1 H), 3.40 (d, J=17.29 Hz, 1 H), 3.69 (d, J=17.29 Hz, 2 H), 3.84 (s, 1 H), 3.91 (d, J=10.51 Hz, 1 H), 4.24 (s, 1 H), 4.83 (m, 2 H), 6.21 (s, 1 H), 7.16 (s, 5 H),
7.24 (m, 1 H), 7.72 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 7.88 (s, 1 H), 8.02 (s, 1 H), 8.16 (s, I H)
Example 375
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.78 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.93 (d, J=6.78 Hz, 3 H), 1.86 (m, 1 H), 2.05 (m, 1 H), 2.64 (dd,
J=14.24, 10.85 Hz, 1 H), 2.84 (m, 1 H), 3.01 (m, 3 H), 3.20 (d, J=17.97 Hz, 1 H), 3.54 (d, J=17.97 Hz, 1 H), 3.81 (m, 1 H), 3.86 (d, J=11.19 Hz, 1 H), 4.23 (m, J=4.41 Hz, 1 H), 4.62 (m, 2 H), 6.06 (d, J=9.83 Hz, 1 H), 7.02 (m, 5 H), 7.32 (m, 4 H), 7.41 (m, 2 H), 7.72 (d, J=8.82 Hz, 2 H), 7.79 (d, J=8.82 Hz, 2 H), 8.16 (s, 1 H) Example 376
Η NMR (300 MHz, CD3OD) δ ppm 0.76 (t, J=6.78 Hz, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 2.00 (m, 1 H), 2.42 (dd, J=13.56, 11.87 Hz, 1 H), 2.59 (s, 3 H), 3.02 (m, 6 H), 3.20 (dd, J=13.73, 3.22 Hz, 1 H), 3.44 (dd, J=14.92, 3.39 Hz, 1 H), 3.68 (d, J=17.97 Hz, 1 H), 3.75 (m, 1 H), 4.01 (d, J=10.85 Hz, 1 H), 4.11 (m, 1 H), 4.73 (d, J=2.71 Hz, 2 H), 6.88 (m, 3 H), 7.07 (m, 2 H), 7.51 (t, J=7.63 Hz, 1 H), 7.66 (d, J=8.14 Hz, 1 H), 7.77 (d, J=8.48 Hz, 2 H), 7.82 (d, J=8.82 Hz, 2 H), 7.94 (d, J=7.80 Hz, 1 H), 8.03 (s, 1 H), 8.14 (s, 1 H) Example 377
Η NMR (300 MHz, CD3OD) δ ppm 0.78 (dd, J=6.44, 4.75 Hz, 6 H), 1.21 (m, 2 H), 1.59 (m, 8 H), 2.01 (m, 1 H), 2.27 (m, 1 H), 2.46 (dd, J=13.56, 11.87 Hz, 1 H), 2.99 (d, J=17.97 Hz, 1 H), 3.07 (m, 1 H), 3.22 (m, 2 H), 3.43 (m, 3 H), 3.48 (m, 1 H), 3.69 (d, J= 7.97 Hz, 1 H), 3.79 (m, 1 H), 4.01 (d, J=11.19 Hz, 1 H), 4.14 (m, 1 H), 4.66 (s, 2 H), 4.77 (d, J=5.76 Hz, 2 H), 6.99 (m, 3 H), 7.13 (m, 2 H), 7.41 (s, 1 H), 7.77 (d, J=8.82 Hz, 2 H), 7.83 (d, J=8.48 Hz, 2 H), 8.14 (s, I H) Example 378
Η NMR (300 MHz, CD3OD) δ ppm 0.79 (m, 6 H), 1.78 (m, 7 H), 1.99 (m, 2 H), 2.47 (dd, J=13.73, 11.70 Hz, 1 H), 2.60 (m, 1 H), 2.66 (s, 3 H), 3.00 (m, 1 H), 3.20 (m, 2 H), 3.40 (m, 2 H), 3.69 (d, J=18.31 Hz, 1 H), 3.76 (m, 1 H), 4.02 (d, J=10.85 Hz, 1 H), 4.13 (m, 1 H), 4.73 (t, J=15.60 Hz, 2 H), 6.99 (m, 3 H), 7.12 (m, 2 H), 7.25 (s, 1 H), 7.77 (d, J=8.48 Hz, 2 H), 7.84 (d, J=4.75 Hz, 2 H), 8.14 (s, 1 H) Example 379 Η NMR (300 MHz, CD3OD) δ ppm 0.79 (t, J=6.27 Hz, 6 H), 1.76 (m, 3 H), 2.00 (m, 4 H), 2.46 (dd, J=13.39, 11.70 Hz, 1 H), 2.62 (m, 1 H), 3.00 (m, 1 H), 3.20 (m, 2 H), 3.43 (m, 2 H), 3.43 (s, 3 H), 3.69 (d, J=18.31 Hz, 1 H), 3.76 (m, 1 H), 4.01 (d, J=10.85 Hz, 1 H), 4.11 (s, 1 H), 4.66 (s, 2 H), 4.77 (d, J=5.76 Hz, 2 H), 6.99 (m, 3 H), 7.13 (dd, J=6.27, 3.56 Hz, 2 H), 7.41 (s, 1 H), 7.77 (d, J=8.82 Hz, 2 H), 7.83 (d, J=8.82 Hz, 2 H), 8.14 (s, 1 H), 8.22 (d, J=9.49 Hz, I H) Example 380
Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.78 Hz, 3 H), 0.83 (d, J=4.75 Hz, 3 H), 0.87 (m, 3 H), 0.93 (d, J=6.78 Hz, 3 H), 1.86 (m, J=7.12 Hz, 1 H), 2.07 (m, 1 H), 2.77 (m, 2 H), 3.04 (m, 3 H), 3.22 (m, 1 H), 3.44 (d, J=18.31 Hz, 1 H), 3.66 (d, J=17.97 Hz, 1 H), 3.88 (m, 2 H), 4.28 (m, 1 H), 4.63 (m, 2 H), 6.12 (d, J=9.49 Hz, 1 H), 7.12 (m, 3 H), 7.22 (m, 2 H), 7.45 (m, 1 H), 7.70 (m, 4 H), 7.82 (d, J=8.48 Hz, 2 H), 8.17 (s, 1 H) Example 381
Η NMR (300 MHz, CDC13) δ ppm 0.82 (dd, J=8.48, 6.78 Hz, 6 H), 0.87 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.78 Hz, 2 H), 1.84 (m, 1 H), 2.09 (m, 1 H), 2.70 (s, 3 H), 2.83 (d, J=13.56 Hz, 1 H), 3.02 (m, 5 H), 3.21 (m, 1 H), 3.21 (s, 1 H), 3.36 (d, J=17.97 Hz, 1 H), 3.65 (d, J=17.97 Hz, 1 H), 3.86 (m, J=10.85 Hz, 2 H), 4.30 (s, 1 H), 4.67 (m, 2 H), 6.15 (d, J=9.49 Hz, 1 H), 7.10 (d, J=7.12 Hz, 3 H), 7.24 (s, 2 H), 7.40 (s, 1 H), 7.72 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.82 Hz, 2 H), 7.95 (s, 1 H), 8.16 (s, 1 H) Example 382
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.78 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.78 Hz, 3 H), 1.81 (m, 1 H), 2.06 (m, 1 H), 2.64 (dd, J=14.41, 10.68 Hz, 1 H), 2.83 (dd, J=13.56, 6.78 Hz, 1 H), 3.03 (m, 2 H), 3.21 (m, 2 H), 3.55 (d, J=17.97 Hz, 1 H), 3.82 (m, 2 H), 3.86 (d, J=l 1.19 Hz, 1 H), 4.24 (m, 1 H), 4.33 (s, 2 H), 4.62 (m, 2 H), 6.08 (d, J=9.16 Hz, 1 H), 7.04 (m, 5 H), 7.24 (s, 1 H), 7.38 (m, 3 H), 7.72 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.82 Hz, 2 H), 8.16 (s, 1 H) Example 383 Η NMR (300 MHz, CDC13) δ ppm 0.81 (m, 6 H), 0.87 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.18 (s, 1 H), 1.84 (m, 2 H), 2.70 (dd, J=14.24, 10.51 Hz, 1 H), 2.84 (dd, J=13.56, 6.44 Hz, 1 H), 3.04 (m, 3 H), 3.22 (m, 1 H), 3.41 (d, J=17.97 Hz, 1 H), 3.61 (d, J=18.31 Hz, 2 H), 3.85 (s, 1 H), 3.96 (d, J=11.19 Hz, 1 H), 4.26 (s, 1 H), 4.57 (d, J=15.26 Hz, 1 H), 4.64 (d, J=14.92 Hz, .1 H), 6.14 (d, J=9.16 Hz, 1 H), 7.11 (m, 5 H), 7.26 (m, 2 H), 7.72 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.82 Hz, 2 H), 8.17 (s, 1 H), 8.59 (s, 2 H) Example 384
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.78 Hz, 4 H), 0.82 (d, J=7.46 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.19 (s, 1 H), 1.85 (m, 2 H), 2.64 (dd, J=14.07, 10.68 Hz, 1 H), 2.86 (dd, J=13.56, 6.78 Hz, 1 H), 3.04 (m, 3 H), 3.20 (m, 1 H), 3.31 (d, J=17.63 Hz, 1 H), 3.56 (d, J=17.97 Hz, 1 H), 3.62 (s, 1 H), 3.78 (s, 1 H), 3.93 (d, J=11.19 Hz, 1 H), 4.23 (m, 1 H), 4.63 (m, 2 H), 6.12 (d, J=8.82 Hz, 1 H), 7.05 (m, 5 H), 7.32 (s, 1 H), 7.74 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.82 Hz, 2 H), 8.09 (s, 1 H), 8.17 (s, 1 H), 8.57 (s, 1 H), 8.73 (s, l H) Example 385 Η NMR (300 MHz, DMSO-d6) δ ppm 0.64 (d, J=6.78 Hz, 3 H), 0.76 (t, J=7.12 Hz, 3 H), 0.86 (m, 1 H), 1.18 (m, 3 H), 1.50 (m, 8 H), 1.74 (s, 1 H), 2.10 (s, 3 H), 2.23 (m, 1 H), 2.37 (m, 1 H), 3.06 (m, 3 H), 3.62 (m, 1 H), 3.77 (d, J=18.31 Hz, 1 H), 3.94 (d, J=9.49 Hz, 1 H), 4.08 (d, J=11.19 Hz, 1 H), 4.58 (s, 2 H), 5.00 (d, J=6.44 Hz, 1 H), 6.90 (s, 1 H), 6.97 (m, 3 H), 7.05 (m, 2 H), 7.77 (d, J=8.82 Hz, 2 H), 7.81 (d, J=8.82 Hz, 2 H), 8.20 (d, J=9.49 Hz, 1 H), 8.24 (s, 1 H) Example 386
Η NMR (300 MHz, DMSO-d6) δ ppm 0.62 (d, J=6.78 Hz, 3 H), 0.76 (t, J=7.12 Hz, 3 H), 0.81 (dd, J=6.61, 1.87 Hz, 6 H), 1.23 (s, 1 H), 1.72 (s, 1 H), 1.96 (s, 1 H), 2.10 (s, 3 H), 2.33 (m, 1 H), 2.88 (m, 1 H), 3.01 (m, 3 H), 3.15 (m, 1 H), 3.26 (d, J=13.56 Hz, 2 H), 3.60 (m, 1 H), 3.76 (d, J=17.97 Hz, 1 H), 3.91 (m, J=9.49 Hz, 1 H), 4.07 (m, 1 H), 4.56 (m, 2 H), 5.00 (d, J=6.44 Hz, 1 H), 6.89 (s, 1 H), 6.95 (m, 3 H), 7.05 (m, 2 H), 7.79 (m, 4 H), 8.20 (d, J=9.49 Hz, 1 H), 8.24 (s, 1 H) Example 387 Η NMR (300 MHz, CDC13) δ ppm 0.81 (d, J=3.73 Hz, 3 H), 0.83 (d, J=3.39 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.85 (m, 1 H), 2.10 (dd, J=11.02, 6.27 Hz, 1 H), 2.71 (dd, J=14.24, 10.51 Hz, 1 H), 2.84 (dd, J=13.56, 6.78 Hz, 1 H), 3.05 (m, 3 H), 3.22 (m, 1 H), 3.40 (d, J=17.97 Hz, 1 H), 3.63 (d, J=3.05 Hz, 1 H), 3.69 (d, J=17.97 Hz, 1 H), 3.81 (d, J=5.43 Hz, 1 H), 3.87 (d, J=l 1.19 Hz, 1 H), 4.24 (dd, J=10.00, 5.26 Hz, 1 H), 4.79 (d, J=15.94 Hz, 1 H), 4.87 (d, J=15.94 Hz, 1 H), 6.10 (d, J=9.49 Hz, 1 H), 7.15 (d, J=7.12 Hz, 5 H), 7.24 (s, 1 H), 7.60 (s, 1 H), 7.73 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.17 (s, 1 H), 8.48 (s, 1 H) Example 388 Η NMR (300 MHz, CDC13) δ ppm 0.78 (t, J=6.61 Hz, 6 H), 0.88 (dd, J=6.78, 3.39 Hz, 6 H), 3.01 (m, 7 H), 2.96 (s, 3 H), 3.03 (m, 1 H), 3.11 (d, J=3.73 Hz, 1 H), 3.51 (m, 2 H), 3.66 (d, J=17.97 Hz, 1 H), 3.97 (s, 2 H), 4.23 (s, 1 H), 4.67 (d, J=7.12 Hz, 1 H), 6.51 (s, 1 H), 6.83 (s,
1 H), 7.09 (s, 1 H), 7.19 (m, J=32.21 Hz, 5 H), 7.73 (d, J=8.48 Hz, 2 H), 7.80 (d, J=8.48 Hz, 2 H), 8.02 (s, 1 H), 8.17 (s, 1 H) Example 389
Η NMR (300 MHz, CD3OD) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.77 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.78 Hz, 3 H), 1.25 (m, 1 H), 2.00 (m, 1 H), 2.35 (s, 2 H), 2.37 (s, 3 H), 2.44 (m, 1 H), 2.91 (m, 1 H), 2.98 (m, 1 H), 3.05 (m, 1 H), 3.12 (m, 1 H), 3.20 (dd, J=13.73, 3.22 Hz, 1 H), 3.44 (dd, J=14.92, 3.39 Hz, 1 H), 3.65 (m, 1 H), 3.74 (m, 2 H), 4.00 (d, J=10.85 Hz, 1 H), 4.04 (s, 1 H), 4.10 (m, 1 H), 4.66 (m, 2 H), 6.87 (m, 3 H), 7.07 (m,
2 H), 7.31 (m, 3 H), 7.38 (s, 1 H), 7.77 (d, J=8.48 Hz, 2 H), 7.83 (d, J=8.48 Hz, 2 H) Example 390
Η NMR (300 MHz, CD3OD) δ ppm 0.73 (d, J=6.78 Hz, 3 H), 0.82 (t, J=7.29 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 0.97 (m, 1 H), 1.24 (t, J=7.12 Hz, 1 H), 1.82 (s, 1 H), 2.01 (s, 1 H), 2.44 (dd, J=13.73, 11.70 Hz, 1 H), 3.03 (m, 5 H), 3.19 (s, 1 H), 3.44 (dd, J=14.92, 3.39 Hz, 1 H), 3.68 (d, J=18.31 Hz, 1 H), 3.76 (s, 1 H), 4.11 (m, 2 H), 4.78 (d, J=5.43 Hz, 2 H), 6.90 (m, 3 H), 7.10 (m, 2 H), 7.63 (t, J=7.80 Hz, 1 H), 7.78 (d, J=8.48 Hz, 2 H), 7.82 (m, 3 H), 8.14 (s, 1 H), 8.18 (d, J=8.48 Hz, 1 H), 8.26 (m, 1 H) Example 391 Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.78 Hz, 3 H), 0.83 (s, 3 H), 0.87 (m, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.08 (m, 1 H), 2.67 (dd, J=14.24, 10.51 Hz, 1 H), 2.83 (dd, J=13.39, 6.61 Hz, 1 H), 3.03 (m, 3 H), 3.03 (m, 3 H), 3.21 (m, 1 H), 3.37 (d, J=17.97 Hz, 1 H), 3.64 (m, 2 H), 3.85 (s, 1 H), 3.88 (d, J=10.85 Hz, 1 H), 4.26 (s, 1 H), 5.08 (m, 2 H), 6.10 (d, J=9.49 Hz, 1 H), 7.06 (m, 5 H), 7.34 (d, J=4.41 Hz, 1 H), 7.64 (m, 1 H), 7.77 (m, 2 H), 8.14 (m, 1 H), 8.16 (s, 1 H), 8.28 (d, J=7.46 Hz, 1 H) Example 392 Η NMR (300 MHz, DMSO-d6) δ ppm 0.63 (d, J=6.78 Hz, 3 H), 0.80 (m, 9 H), 0.94 (s, 1 H), 1.34 (dd, J=10.34, 3.22 Hz, 1 H), 1.80 (s, 1 H), 1.97 (m, 1 H), 2.37 (m, 1 H), 3.04 (m, 5 H), 3.58 (s, 1 H), 3.83 (d, J=17.97 Hz, 1 H), 4.08 (m, 2 H), 4.80 (t, J=16.28 Hz, 2 H), 5.01 (d, J=6.78 Hz, 1 H), 5.53 (s, 2 H), 6.78 (d, J=2.37 Hz, 1 H), 6.96 (m, 1 H), 7.07 (m, 5 H), 7.23 (d, J=8.82 Hz, 1 H), 7.53 (d, J=9.16 Hz, 1 H), 7.79 (m, 4 H), 7.93 (d, J=8.48 Hz, 1 H), 8.24 (s, 1 H), 8.25 (d, J=9.49 Hz, 1 H) Example 393
Η NMR (300 MHz, CD3OD) δ ppm 0.74 (d, J=6.78 Hz, 3 H), 0.83 (d, J=7.12 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 0.97 (d, J=8.48 Hz, 1 H), 1.29 (s, 1 H), 1.84 (s, 1 H), 2.02 (s, 1 H), 2.47 (dd, J=13.73, 11.70 Hz, 1 H), 2.65 (s, 3 H), 3.08 (m, 6 H), 3.45 (dd, J=14.75, 3.56 Hz, 1 H), 3.74 (m, 1 H), 3.77 (m, 1 H), 4.12 (m, 2 H), 4.74 (m, 2 H), 6.97 (m, 3 H), 7.13 (dd, J=6.78, 3.05 Hz, 2 H), 7.56 (dd, J=5.09, 1.70 Hz, 1 H), 7.77 (d, J=8.48 Hz, 2 H), 7.83 (d, J=8.48 Hz, 2 H), 7.95 (s, 1 H), 8.14 (s, 1 H), 8.65 (d, J=4.75 Hz, 1 H) Example 394 Η NMR (300 MHz, DMSO-d6) δ ppm 0.65 (d, J=6.78 Hz, 3 H), 0.76 (t, J=6.95 Hz, 3 H), 0.85 (m, 1 H), 1.23 (m, 1 H), 1.61 (m, 2 H), 1.73 (m, 4 H), 1.87 (m, 2 H), 2.10 (s, 3 H), 2.38 (dd, J=13.05, 11.36 Hz, 1 H), 2.57 (m, 1 H), 3.11 (m, 6 H), 3.57 (s, 1 H), 3.77 (d, J=18.31 Hz, 1 H), 3.92 (d, J=5.76 Hz, 1 H), 4.09 (d, J=10.85 Hz, 1 H), 4.58 (s, 2 H), 5.04 (d, J=6.44 Hz, 1 H), 6.90 (s, 1 H), 6.96 (m, 3 H), 7.06 (m, 2 H), 7.78 (m, 4 H), 8.20 (d, J=9.49 Hz, 1 H) Example 395
Η NMR (300 MHz, DMSO-d6) δ ppm 0.70 (d, J=6.78 Hz, 3 H), 0.76 (d, J=6.44 Hz, 3 H), 0.90 (m, 1 H), 1.69 (m, 4 H), 1.95 (m, 2 H), 2.39 (m, 1 H), 2.57 (m, 1 H), 3.03 (m, 4 H), 3.23 (m, 1 H), 3.60 (m, 1 H), 3.84 (m, 2 H), 3.91 (s, 3 H), 4.04 (m, 2 H), 4.14 (m, 1 H), 5.00 (m, 2 H), 6.98 (m, 1 H), 7.11 (dd, J=7.97, 4.24 Hz, 3 H), 7.23 (m, 2 H), 7.79 (d, J=2.71 Hz, 4 H), 7.90 (m, 1 H), 8.24 (s, 1 H), 8.33 (dd, J=4.92, 1.53 Hz, 1 H) Example 396
Η NMR (300 MHz, DMSO-d6) δ ppm 0.69 (d, J=6.44 Hz, 3 H), 0.75 (d, J=6.78 Hz, 3 H), 1.12 (s, 2 H), 1.50 (m, 8 H), 1.97 (m, 1 H), 2.26 (m, 1 H), 2.38 (dd, J=12.89, 11.53 Hz, 1 H), 3.07 (m, 5 H), 3.60 (s, 1 H), 3.84 (m, 1 H), 3.91 (s, 3 H), 4.03 (d, J=10.85 Hz, 1 H), 5.01 (d, J=6.44 Hz, 3 H), 6.98 (m, 1 H), 7.12 (d, J=4.41 Hz, 3 H), 7.22 (m, 2 H), 7.78 (m, 4 H), 7.90 (dd, J=8.14, 1.36 Hz, 1 H), 8.24 (s, 1 H), 8.33 (dd, J=4.75, 1.36 Hz, 1 H) Example 397
Η NMR (300 MHz, CDC13) δ ppm 0.77 (m, 3 H), 0.86 (m, 6 H), 0.92 (d, J=6.44 Hz, 3 H), 0.96 (s, 1 H), 1.26 (t, J=7.12 Hz, 1 H), 1.83 (m, 2 H), 2.71 (dd, J=14.07, 10.34 Hz, 1 H), 2.85 (dd, J=13.56, 6.78 Hz, 1 H), 3.04 (m, 4 H), 3.21 (m, 1 H), 3.44 (d, J=17.63 Hz, 1 H), 3.67 (d, J=17.97 Hz, 1 H), 3.75 (s, 1 H), 3.83 (s, 1 H), 3.99 (d, J=10.85 Hz, 1 H), 4.25 (d, J=5.76 Hz, 1 H), 4.80 (m, 2 H), 6.22 (s, 1 H), 7.15 (s, 5 H), 7.22 (d, J=7.12 Hz, 1 H), 7.64 (m, 1 H), 7.72 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 7.85 (m, 1 H), 8.16 (s, 1 H), 8.52 (d, J=3.73 Hz, I H) Example 398
Η NMR (300 MHz, CDC13) δ ppm 0.81 (m, 6 H), 0.87 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.26 (t, J=7.12 Hz, 1 H), 1.86 (s, 2 H), 2.68 (s, 1 H), 2.84 (dd, J=13.56, 7.12 Hz, 1 H), 3.01 (m, 3 H), 3.20 (s, 1 H), 3.44 (d, J=17.97 Hz, 1 H), 3.64 (m, 2 H), 3.85 (s, 1 H), 3.98 (d, J=11.19 Hz, 1 H), 4.26 (s, 1 H), 5.09 (d, J=5.09 Hz, 2 H), 6.16 (d, J=8.14 Hz, 1 H), 7.07 (m, 6 H), 7.41 (s, 1 H), 7.71 (m, J=8.14 Hz, 3 H), 7.80 (m, 2 H), 7.87 (s, 1 H), 8.16 (s, 1 H), 8.24 (d, J=6.44 Hz, 1 H), 8.31 (d, J=8.48 Hz, 1 H) Example 399
Η NMR (300 MHz, CDC13) δ ppm 0.82 (t, J=7.29 Hz, 6 H), 0.95 (m, 1 H), 1.26 (t, J=7.12 Hz, 1 H), 1.70 (m, 2 H), 1.92 (m, 4 H), 2.49 (m, 1 H), 2.70 (dd, J=14.24, 10.51 Hz, 1 H), 3.07 (m, 4 H), 3.25 (m, 1 H), 3.44 (d, J=17.97 Hz, 1 H), 3.50 (d, J=2.37 Hz, 1 H), 3.64 (d, J=17.97 Hz, 1 H), 3.82 (s, 1 H), 4.00 (d, J=11.19 Hz, 1 H), 4.28 (s, 1 H), 5.09 (d, J=4.41 Hz, 2 H), 6.22 (d, J=9.49 Hz, 1 H), 7.06 (m, 5 H), 7.38 (d, J=3.73 Hz, 1 H), 7.65 (d, J=7.12 Hz, 1 H), 7.71 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 7.99 (s, 1 H), 8.16 (s, 1 H), 8.20 (d, J=8.48 Hz, 1 H), 8.29 (d, J=8.48 Hz, 1 H), 8.89 (d, J=4.07 Hz, 1 H) Example 400 Η NMR (300 MHz, CDC13) δ ppm 0.80 (d, J=6.44 Hz, 3 H), 0.83 (m, 3 H), 0.96 (m, 1 H), 1.23 (m, 2 H), 1.58 (m, 8 H), 1.93 (m, 1 H), 2.10 (m, 1 H), 2.69 (dd, J=14.41, 10.68 Hz, 1 H), 3.07 (m, 3 H), 3.43 (d, J=17.97 Hz, 1 H), 3.63 (m, 2 H), 3.89 (m, 1 H), 3.99 (d, J=11.19 Hz, 1 H), 4.27 (m, 1 H), 5.08 (m, 2 H), 6.19 (d, J=9.49 Hz, 1 H), 7.06 (m, 5 H), 7.36 (d, J=4.41 Hz, 1 H), 7.65 (m, 2 H), 7.72 (m, 2 H), 7.77 (d, J=8.48 Hz, 2 H), 8.17 (m, 1 H), 8.16 (s, 1 H), 8.29 (d, J=8.48 Hz, 1 H), 8.88 (d, J=4.41 Hz, 1 H) Example 401
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.84 (dd, J=8.31, 6.61 Hz, 1 H), 2.06 (m, 1 H), 2.63 (dd, J=14.07, 10.68 Hz, 1 H), 2.84 (dd, J=13.56, 6.78 Hz, 1 H), 3.03 (m, 4 H), 3.22 (m, 2 H), 3.55 (d, J=17.63 Hz, 1 H), 3.67 (s, 1 H), 3.82 (d, J=2.71 Hz, 1 H), 3.86 (d, J=10.85 Hz, 1 H), 4.19 (m, 1 H), 4.49 (d, J=14.24 Hz, 1 H), 4.52 (d, J=14.24 Hz, 1 H), 6.14 (d, J=9.16 Hz, 1 H), 6.60 (dd, J=7.63, 1.86 Hz, 1 H), 6.76 (s, 1 H), 6.80 (d, J=7.80 Hz, 1 H), 7.04 (m, 5 H), 7.10 (m, 1 H), 7.72 (d, J=8.48 Hz, 2 H), 7.79 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H) Example 402 Η NMR (300 MHz, CD3OD) δ ppm 0.76 (m, 6 H), 0.87 (d, J=6.44 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 2.01 (m, 1 H), 2.21 (s, 3 H), 2.41 (dd, J=13.56, 11.87 Hz, 1 H), 3.06 (m, 7 H), 3.44 (m, 1 H), 3.65 (d, J=17.97 Hz, 1 H), 3.75 (m, 1 H), 4.00 (d, J=11.19 Hz, 1 H), 4.11 (m, 1 H), 4.67 (s, 2 H), 6.85 (m, 3 H), 7.06 (m, 2 H), 7.39 (m, 2 H), 7.59 (m, 1 H), 7.72 (s, 1 H), 7.77 (d, J=8.82 Hz, 2 H), 7.83 (d, J=8.48 Hz, 2 H), 8.14 (s, 1 H) Example 403
Η NMR (300 MHz, CD3OD) δ ppm 0.75 (d, J=6.78 Hz, 3 H), 0.78 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.78 Hz, 3 H), 1.29 (s, 2 H), 2.02 (m, 2 H), 2.44 (dd, J=13.56, 11.87 Hz, 1 H), 2.98 (m, 3 H), 3.11 (m, 1 H), 3.20 (m, 1 H), 3.44 (m, 1 H), 3.67 (m, 1 H), 3.76 (m, 1 H), 3.86 (d, J=4.07 Hz, 2 H), 4.00 (d, J=10.85 Hz, 1 H), 4.12 (m, 1 H), 4.66 (m, 1 H), 4.79 (s, 2 H), 6.89 (m, 3 H), 7.08 (m, 2 H), 7.32 (m, 3 H), 7.40 (s, 1 H), 7.77 (d, J=8.82 Hz, 2 H), 7.83 (d, J=8.48 Hz, 2 H), 8.14 (s, 1 H) Example 404
Η NMR (300 MHz, CD3OD) δ ppm 0.73 (d, J=6.44 Hz, 3 H), 0.82 (t, J=7.29 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 1.24 (m, 2 H), 1.80 (s, 1 H), 2.01 (m, 1 H), 2.41 (dd, J=13.73, 11.70 Hz, 1 H), 0.00 (none, 3 H), 3.11 (m, 1 H), 3.20 (dd, J=13.56, 3.39 Hz, 2 H), 3.44 (dd, J=14.75, 3.56 Hz, 1 H), 3.60 (d, J 7.97 Hz, 1 H), 3.75 (m, 1 H), 4.11 (m, 2 H), 4.53 (s, 2 H), 6.64 (m, 1 H), 6.64 (m, 1 H), 6.71 (d, J=7.46 Hz, 1 H), 6.71 (d, J=7.46 Hz, 1 H), 6.77 (d, J=1.70 Hz, 1 H), 6.77 (d, J=1.70 Hz, 1 H), 6.90 (m, 5 H), 6.90 (m, 3 H), 7.07 (m, 4 H), 7.83 (d, J=8.48 Hz, 2 H), 8.14 (s, 1 H) Example 405 Η NMR (300 MHz, CD3OD) δ ppm 0.74 (d, J=6.78 Hz, 3 H), 0.82 (t, J=7.46 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.27 (dd, J=13.90, 4.41 Hz, 1 H), 1.83 (s, 1 H), 2.01 (m, 1 H), 2.25 (s, 3 H), 2.46 (dd, J=13.73, 11.70 Hz, 1 H), 3.03 (m, 6 H), 3.21 (dd, J=13.56, 3.39 Hz, 1 H), 3.45 (dd, J=14.75, 3.56 Hz, 1 H), 3.71 (d, J=17.97 Hz, 1 H), 3.77 (m, 1 H), 4.13 (m, 2 H), 4.70 (d, J=7.80 Hz, 2 H), 6.94 (m, 3 H), 7.11 (m, 2 H), 7.32 (dd, J=5.09, 1.70 Hz, 1 H), 7.80 (q, J=8.48 Hz, 4 H), 7.85 (d, J=3.73 Hz, 1 H), 8.14 (s, 1 H), 8.51 (d, J=5.09 Hz, 1 H) Example 436
Η NMR (300 MHz, CDC13) δ ppm 0.85 (m, 12 H), 1.91 (m, 1 H), 2.22 (s, 1 H), 2.95 (m, 7 H), 2.98 (s, 3 H), 3.36 (dd, J=15.26, 4.41 Hz, 1 H), 3.85 (s, 1 H), 4.11 (m, 1 H), 4.22 (s, 1 H), 4.31 (d, J=15.94 Hz, 1 H), 7.18 (m, 5 H), 7.29 (s, 1 H), 7.70 (d, J=8.48 Hz, 2 H), 7.76 (s, 1 H), 7.82 (d, J=8.48 Hz, 2 H), 8.13 (s, 1 H), 8.29 (s, 1 H), 8.51 (s, 1 H) Example 437
Η NMR (300 MHz, CDC13) δ ppm 0.68 (d, J=6.78 Hz, 3 H), 0.87 (m, 9 H), 1.89 (dd, J=13.73, 6.95 Hz, 1 H), 2.23 (m, 1 H), 2.68 (s, 3 H), 2.85 (dd, J=13.39, 7.29 Hz, 1 H), 2.93 (s, 3 H), 3.02 (m, 4 H), 3.35 (dd, J=15.09, 4.58 Hz, 1 H), 3.85 (m, 1 H), 4.10 (d, J=4.75 Hz, 1 H), 4.21 (d, J=15.94 Hz, 2 H), 4.53 (d, J=15.94 Hz, 1 H), 6.16 (s, 1 H), 6.76 (s, 1 H), 6.96 (s, 1 H), 7.18 (m, 5 H), 7.71 (d, J=8.48 Hz, 2 H), 7.82 (d, J=8.48 Hz, 2 H), 8.13 (s, 1 H) Example 438 Η NMR (300 MHz, CDC13) δ ppm 0.67 (d, J=6.78 Hz, 3 H), 0.87 (m, 9 H), 1.69 (s, 1 H), 1.89 (m, 1 H), 2.20 (s, 1 H), 2.86 (dd, J=13.56, 7.46 Hz, 1 H), 2.94 (s, 3 H), 3.02 (m, 3 H), 3.33 (dd, J=15.26, 4.75 Hz, 1 H), 3.50 (s, 3 H), 3.85 (m, 1 H), 4.09 (s, 1 H), 4.22 (s, 1 H), 4.28 (d, J=16.28 Hz, 1 H), 4.56 (d, J=16.62 Hz, 1 H), 4.68 (s, 2 H), 6.77 (s, 1 H), 7.11 (s, 1 H), 7.20 (m, 5 H), 7.71 (d, J=8.48 Hz, 2 H), 7.82 (d, J=8.48 Hz, 2 H), 8.13 (s, 1 H) Example 439
Η NMR (300 MHz, DMSO-d6) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.99 (t, J=6.95 Hz, 3 H), 1.08 (d, J=7.12 Hz, 3 H), 1.29 (d, J=6.78 Hz, 6 H), 1.96 (m, 1 H), 2.57 (dd, J=13.90, 10.51 Hz, 1 H), 2.85 (m, 2 H), 3.02 (m, 2 H), 3.26 (m, 6 H), 3.78 (m, 2 H), 4.10 (m, 1 H), 6.38 (s, 1 H), 7.12 (m, 5 H), 7.22 (s, 1 H), 7.62 (d, J=8.82 Hz, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.80 (d, J=8.82 Hz, 2 H), 8.23 (s, 1 H) Example 440
Η NMR (300 MHz, CD3OD) δ ppm 0.76 (d, J=3.39 Hz, 3 H), 0.78 (d, J=3.39 Hz, 3 H), 1.13 (m, 2 H), 1.26 (m, 2 H), 1.37 (d, J=6.78 Hz, 6 H), 1.59 (m, 8 H), 1.90 (m, 1 H), 2.23 (dd, J=15.09, 7.63 Hz, 1 H), 2.65 (dd, J=13.90, 10.51 Hz, 1 H), 2.94 (s, 3 H), 3.07 (m, 2 H), 3.21 (m, 1 H), 3.46 (dd, J=14.92, 3.73 Hz, 1 H), 3.82 (m, 1 H), 3.96 (d, J=7.46 Hz, 1 H), 4.10 (m, 1 H), 4.48 (m, 2 H), 7.15 (m, 6 H), 7.76 (d, J=8.82 Hz, 2 H), 7.81 (d, J=8.82 Hz, 2 H), 8.13 (s, l H) Example 441 Η NMR (300 MHz, CD3OD) δ ppm 0.76 (d, J=3.05 Hz, 3 H), 0.78 (d, J=3.05 Hz, 3 H), 1.36 (d, J=6.78 Hz, 6 H), 1.66 (m, 2 H), 1.78 (m, 2 H), 1.96 (m, 4 H), 2.58 (dd, J=14.92, 7.46 Hz,
1 H), 2.65 (m, 1 H), 2.94 (s, 3 H), 3.11 (m, 6 H), 3.42 (dd, J=14.75, 3.90 Hz, 1 H), 3.78 (m, 1 H), 3.95 (d, J=7.46 Hz, 1 H), 4.08 (m, 1 H), 4.48 (m, 2 H), 7.15 (m, 6 H), 7.77 (d, J=8.82 Hz,
2 H), 7.82 (d, J=8.48 Hz, 2 H), 8.14 (s, 1 H) Example 442
Η NMR (300 MHz, CD3OD) δ ppm 0.71 (d, J=6.78 Hz, 3 H), 0.78 (t, J=7.46 Hz, 3 H), 0.97 (m, 1 H), 1.14 (d, J=6.10 Hz, 1 H), 1.24 (m, 2 H), 1.61 (m, 8 H), 2.24 (m, 1 H), 2.66 (dd, J=14.07, 10.68 Hz, 1 H), 2.94 (s, 3 H), 3.12 (m, 5 H), 3.47 (dd, J=14.92, 3.73 Hz, 1 H), 3.83 (m, 1 H), 4.01 (d, J=7.46 Hz, 1 H), 4.13 (m, 1 H), 4.55 (s, 2 H), 7.16 (m, 5 H), 7.31 (t, J=7.46 Hz, 2 H), 7.77 (m, 3 H), 7.82 (d, J=6.44 Hz, 2 H), 8.13 (s, 1 H), 8.48 (d, J=4.07 Hz, 1 H) Example 443
Η NMR (300 MHz, CD3OD) δ ppm 0.71 (d, J=6.78 Hz, 3 H), 0.78 (m, 3 H), 0.98 (m, 1 H), 1.24 (m, 1 H), 1.73 (m, 5 H), 1.96 (m, 2 H), 2.57 (dd, J=15.26, 7.46 Hz, 1 H), 2.66 (m, 2 H), 2.94 (s, 3 H), 3.02 (dd, J=14.75, 8.65 Hz, 1 H), 3.17 (m, 2 H), 3.43 (m, 1 H), 3.79 (m, 1 H), 4.01 (m, 2 H), 4.12 (m, 1 H), 4.55 (s, 2 H), 6.23 (d, J=7.80 Hz, 1 H), 7.16 (m, 5 H), 7.31 (m, J=7.12, 7.12 Hz, 2 H), 7.78 (m, 3 H), 7.83 (d, J=8.82 Hz, 2 H), 8.13 (s, 1 H), 8.48 (d, J=4.41 Hz, I H) Example 444
Η NMR (300 MHz, DMSO-d6) δ ppm 0.85 (d, J=6.44 Hz, 3 H), 1.03 (s, 9 H), 1.08 (m, 1 H), 1.57 (d, J=28.14 Hz, 1 H), 1.71 (m, 1 H), 1.76 (s, 1 H), 1.84 (d, J=20.35 Hz, 1 H), 2.54 (m, 1 H), 2.67 (dd, J=13.73, 9.66 Hz, 1 H), 2.87 (s, 3 H), 2.97 (m, 1 H), 3.08 (m, 1 H), 3.25 (d, J=7.80 Hz, 1 H), 3.35 (d, J=4.07 Hz, 1 H), 3.38 (s, 3 H), 3.61 (s, 1 H), 3.81 (m, 1 H), 3.93 (dd, J=6.44, 4.41 Hz, 1 H), 4.00 (s, 1 H), 4.47 (d, J=4.41 Hz, 2 H), 4.65 (s, 2 H), 5.05 (d, J=6.44 Hz, 1 H), 5.80 (d, J=6.78 Hz, 1 H), 7.15 (m, 1 H), 7.22 (m, 5 H), 7.37 (s, 1 H), 7.40 (d, J=9.16 Hz, 1 H), 7.77 (d, J=8.48 Hz, 2 H), 7.81 (d, J=8.82 Hz, 2 H), 8.24 (s, 1 H) Example 445 Η NMR (300 MHz, DMSO-d6) δ ppm 0.84 (d, J=6.44 Hz, 3 H), 1.03 (s, 9 H), 1.08 (m, 2 H), 1.19 (m, 2 H), 1.50 (s, 6 H), 2.19 (s, 1 H), 2.87 (s, 3 H), 2.96 (m, 2 H), 3.14 (dd, J=14.07, 8.65 Hz, 1 H), 3.38 (s, 3 H), 3.65 (t, J=10.85 Hz, 1 H), 3.81 (dd, J=6.10, 4.41 Hz, 1 H), 3.94 (dd, J=6.61, 4.58 Hz, 1 H), 4.03 (s, 1 H), 4.47 (d, J=4.41 Hz, 2 H), 4.65 (s, 2 H), 5.02 (d, J=6.44 Hz, 1 H), 5.80 (d, J=6.78 Hz, 1 H), 7.16 (m, 1 H), 7.20 (d, J=8.14 Hz, 5 H), 7.23 (s, 1 H), 7.38 (m, 1 H), 7.76 (d, J=8.48 Hz, 2 H), 7.81 (d, J=8.48 Hz, 2 H) Example 446
Η NMR (300 MHz, DMSO-d6) δ ppm 0.59 (d, J=6.44 Hz, 3 H), 0.70 (t, J=7.29 Hz, 3 H), 1.27 (m, 2 H), 1.56 (m, 3 H), 1.74 (m, 2 H), 1.86 (m, 2 H), 2.57 (m, 1 H), 2.85 (s, 3 H), 2.92 (m, 1 H), 3.01 (m, 1 H), 3.07 (m, 1 H), 3.26 (m, 1 H), 3.38 (s, 3 H), 3.60 (m, J=4.41 Hz, 1 H), 3.94 (t, J=7.97 Hz, 2 H), 4.41 (d, J=15.94 Hz, 1 H), 4.51 (d, J=16.28 Hz, 1 H), 4.64 (s, 2 H), 5.02 (d, J=6.10 Hz, 1 H), 5.98 (d, J=8.48 Hz, 1 H), 7.14 (m, 5 H), 7.32 (s, 1 H), 7.67 (d, J=8.82 Hz, 1 H), 7.79 (t, J=8.82 Hz, 4 H) Example 447 Η NMR (300 MHz, DMSO-d6) δ ppm 0.59 (d, J=6.78 Hz, 3 H), 0.70 (t, J=7.46 Hz, 3 H), 0.88 (m, 1 H), 1.07 (m, 1 H), 1.24 (m, 2 H), 1.52 (m, 8 H), 2.57 (m, 1 H), 2.84 (s, 3 H), 2.98 (m, 2 H), 3.13 (m, 1 H), 3.28 (s, 1 H), 3.38 (s, 3 H), 3.61 (s, 1 H), 3.95 (t, J=8.14 Hz, 2 H), 4.41 (d, J=16.28 Hz, 1 H), 4.50 (d, J=16.28 Hz, 1 H), 4.64 (s, 2 H), 4.99 (d, J=6.10 Hz, 1 H), 5.97 (d, J=8.14 Hz, 1 H), 7.14 (m, 5 H), 7.31 (s, 1 H), 7.69 (d, J=9.16 Hz, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.78 (d, J=8.82 Hz, 2 H), 8.23 (s, 1 H) Example 448
Η NMR (300 MHz, CD3OD) δ ppm 0.77 (dd, J=6.78, 1.70 Hz, 6 H), 0.98 (m, 1 H), 1.64 (m, 2 H), 1.80 (m, 2 H), 1.96 (m, 4 H), 2.59 (m, 2 H), 2.67 (s, 3 H), 2.70 (m, 1 H), 2.93 (s, 3 H), 2.99 (m, 1 H), 3.17 (m, 2 H), 3.43 (dd, J=14.75, 3.90 Hz, 1 H), 3.78 (m, 1 H), 3.96 (d, J=7.12 Hz, 1 H), 4.10 (m, 1 H), 4.43 (d, J=15.94 Hz, 1 H), 4.52 (d, J=16.28 Hz, 1 H), 7.16 (m, 6 H), 7.77 (d, J=8.48 Hz, 2 H), 7.82 (d, J=8.82 Hz, 2 H), 8.14 (s, 1 H) Example 449 Η NMR (300 MHz, DMSO-d6) δ ppm 0.59 (d, J=6.78 Hz, 3 H), 0.69 (t, J=7.46 Hz, 3 H), 0.77 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.93 (m, 1 H), 1.19 (m, 1 H), 1.59 (s, 1 H), 1.96 (m, 1 H), 2.60 (s, 3 H), 2.83 (s, 3 H), 2.90 (m, 1 H), 2.98 (m, 1 H), 3.03 (m, 1 H), 3.31 (m, 2 H), 3.59 (s, 1 H), 3.95 (m, 2 H), 4.35 (d, J=16.28 Hz, 1 H), 4.47 (d, J=15.94 Hz, 1 H), 4.97 (d, J=6.44 Hz, 1 H), 6.02 (d, J=8.48 Hz, 1 H), 7.14 (m, 6 H), 7.67 (d, J=9.16 Hz, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.80 (d, J=8.82 Hz, 2 H), 8.23 (s, 1 H) Example 450
Η NMR (300 MHz, CDC13) δ ppm 0.76 (t, J=7.29 Hz, 3 H), 0.84 (d, J=7.12 Hz, 3 H), 0.96 (m, 1 H), 1.66 (m, 2 H), 1.83 (m, 3 H), 1.98 (m, 4 H), 2.52 (dd, J=14.92, 7.46 Hz, 1 H), 2.65 (s, 3 H), 2.91 (s, 3 H), 3.03 (m, 2 H), 3.25 (m, 1 H), 3.41 (dd, J=14.75, 5.93 Hz, 1 H), 3.82 (m, 1 H), 4.17 (d, J=16.28 Hz, 1 H), 4.24 (m, 3 H), 4.53 (d, J=16.28 Hz, 1 H), 6.23 (s, 1 H), 6.82 (d, J=8.14 Hz, 1 H), 6.95 (s, 1 H), 7.19 (m, 5 H), 7.73 (d, J=8.48 Hz, 2 H), 7.85 (d, J=8.48 Hz, 2 H), 8.14 (s, 1 H) Example 451 Η NMR (300 MHz, DMSO-d6) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.83 (dd, J=8.14, 6.44 Hz, 6 H), 1.02 (s, 9 H), 1.95 (m, 1 H), 2.62 (s, 3 H), 2.68 (dd, J=13.90, 9.49 Hz, 1 H), 2.86 (s, 3 H), 2.93 (m, 4 H), 3.62 (s, 1 H), 3.79 (dd, J=10.85, 6.44 Hz, 1 H), 3.94 (dd, J=6.61, 4.58 Hz, 1 H), 4.03 (m, 1 H), 4.42 (t, J=16.62 Hz, 2 H), 5.01 (d, J=6.44 Hz, 1 H), 5.84 (d, J=6.44 Hz, 1 H), 7.16 (m, 5 H), 7.22 (s, 1 H), 7.36 (d, J=9.49 Hz, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.80 (d, J=8.82 Hz, 2 H), 8.23 (s, 1 H) Example 452
Η NMR (300 MHz, DMSO-d6) δ ppm 0.85 (d, J=6.10 Hz, 3 H), 1.03 (s,,9 H), 1.57 (d, J=27.13 Hz, 2 H), 1.71 (m, 3 H), 1.87 (s, 2 H), 2.62 (s, 3 H), 2.68 (dd, J=13.90, 9.83 Hz, 1 H), 2.86 (s, 3 H), 2.95 (m, 2 H), 3.08 (m, 1 H), 3.26 (m, 1 H), 3.61 (s, 1 H), 3.81 (dd, J=6.10, 4.41 Hz, 1 H), 3.93 (dd, J=6.44, 4.41 Hz, 2 H), 4.38 (d, J=16.28 Hz, 1 H), 4.42 (d, J=16.28 Hz, 2 H), 5.05 (d, J=6.10 Hz, 1 H), 5.85 (d, J=6.44 Hz, 1 H), 7.17 (m, 5 H), 7.23 (s, 1 H), 7.38 (d, J=9.16 Hz, 1 H), 7.77 (d, J=8.82 Hz, 2 H), 7.81 (d, J=8.48 Hz, 2 H), 8.23 (s, 1 H) Example 453 Η NMR (300 MHz, CDC13) δ ppm 0.79 (t, J=6.44 Hz, 6 H), 0.87 (d, J=6.78 Hz, 6 H), 1.16 (m, 1 H), 1.52 (s, 1 H), 1.88 (m, 1 H), 2.88 (s, 3 H), 2.94 (d, J=11.19 Hz, 1 H), 3.07 (m, 2 H), 3.07 (m, 2 H), 3.21 (m, 1 H), 3.87 (m, 1 H), 3.99 (d, J=3.73 Hz, 1 H), 4.13 (dd, J=7.63, 5.93 Hz, 1 H), 4.23 (m, 1 H), 4.45 (d, J=15.94 Hz, 1 H), 4.67 (m, 2 H), 6.43 (d, J=8.14 Hz, 1 H), 7.21 (m, 5 H), 7.51 (m, 2 H), 7.70 (d, J=6.44 Hz, 2 H), 7.71 (s, 1 H), 7.79 (d, J=8.48 Hz, 2 H), 8.05 (s, 1 H), 8.14 (s, 1 H) Example 454
Η NMR (300 MHz, CD3OD) δ ppm 0.71 (d, J=6.78 Hz, 3 H), 0.78 (t, J=7.46 Hz, 3 H), 0.85 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.78 Hz, 3 H), 0.97 (m, 1 H), 1.28 (m, 1 H), 1.64 (s, 1 H), 2.00 (m, 1 H), 2.61 (dd, J=13.90, 10.85 Hz, 1 H), 2.94 (s, 3 H), 3.07 (m, 7 H), 3.46 (dd, J=14.92, 3.73 Hz, 1 H), 3.83 (s, 3 H), 3.96 (d, J=8.14 Hz, 1 H), 4.09 (m, 1 H), 4.23 (d, J=16.28 Hz, 1 H), 4.38 (d, J=16.28 Hz, 1 H), 6.81 (s, 1 H), 7.09 (m, 5 H), 7.80 (q, J=8.48 Hz, 4 H), 7.87 (m, 1 H), 8.13 (s, 1 H) Example 455
Η NMR (300 MHz, DMSO d6) δ ppm 0.65 (dd, J=9.16, 6.78 Hz, 6 H), 1.57 (dd, J=16.62, 8.82 Hz, 2 H), 1.71 (m, 2 H), 1.84 (dd, J=13.73, 6.61 Hz, 4 H), 2.56 (m, J=20.01 Hz, 1 H), 2.85 (s, 3 H), 2.91 (m, 1 H), 3.00 (m, 1 H), 3.07 (m, 1 H), 3.26 (d, J=9.83 Hz, 2 H), 3.37 (s, 3 H), 3.60 (d, J=3.05 Hz, 1 H), 3.90 (m, 2 H), 4.42 (d, J=16.28 Hz, 1 H), 4.51 (d, J=16.28 Hz, 1 H), 4.64 (s, 2 H), 5.03 (d, J=6.44 Hz, 1 H), 5.96 (d, J=8.48 Hz, 1 H), 7.14 (m, 5 H), 7.32 (s, 1 H), 7.70 (d, J=9.49 Hz, 1 H), 7.78 (m, 4 H), 8.23 (s, 1 H) Example 456
Η NMR (300 MHz, CD3OD) δ ppm 0.74 (t, J=7.29 Hz, 3 H), 0.80 (d, J=7.12 Hz, 3 H), 0.93 (m, 1 H), 1.29 (s, 1 H), 1.66 (dd, J=16.62, 9.16 Hz, 2 H), 1.81 (m, 2 H), 1.97 (m, 2 H), 2.61 (m, 1 H), 2.86 (s, 3 H), 2.99 (d, J=2.03 Hz, 3 H), 3.03 (m, 1 H), 3.12 (m, 3 H)> 3.16 (m, 2 H), 3.44 (dd, J=14.58, 4.07 Hz, 1 H), 3.80 (m, 1 H), 3.98 (m, 1 H), 4.10 (s, 1 H), 4.28 (d, J=15.94 Hz, 1 H), 4.36 (d, J=15.94 Hz, 1 H), 6.16 (s, 1 H), 6.84 (s, 1 H), 7.06 (m, 3 H), 7.18 (m, 2 H), 7.80 (q, J=8.59 Hz, 4 H), 7.87 (d, J=9.16 Hz, 1 H), 8.14 (s, 1 H) Example 457 Η NMR (300 MHz, CD3OD) δ ppm 0.69 (d, J=6.44 Hz, 3 H), 0.80 (t, J=7.29 Hz, 3 H), 0.85 (d, J=6.78 Hz, 3 H), 0.89 (d, J=6.78 Hz, 3 H), 0.99 (m, 1 H), 1.35 (m, 1 H), 1.64 (m, 1 H), 2.00 (m, 1 H), 2.63 (dd, J=13.90, 10.85 Hz, 1 H), 2.86 (s, 3 H), 2.95 (m, 1 H), 3.06 (m, 2 H), 3.15 (m, 2 H), 3.28 (s, 1 H), 3.46 (dd, J=14.92, 3.39 Hz, 1 H), 3.79 (m, 1 H), 4.00 (d, J=8.48 Hz, 1 H), 4.09 (m, 1 H), 4.45 (d, J=15.94 Hz, 1 H), 4.62 (d, J=15.94 Hz, 1 H), 7.15 (m, 5 H), 7.39 (dd, J=7.46, 4.41 Hz, 1 H), 7.70 (m, 1 H), 7.79 (q, J=8.82 Hz, 4 H), 8.13 (s, 1 H), 8.43 (dd, J=4.92, 1.53 Hz, 2 H) Example 458
Η NMR (300 MHz, CD3OD) δ ppm 0.70 (d, J=6.44 Hz, 3 H), 0.80 (t, J=7.29 Hz, 3 H), 1.00 (m, 1 H), 1.35 (m, 1 H), 1.66 (m, 2 H), 1.80 (m, 3 H), 1.95 (m, 3 H), 1.95 (m, 2 H), 2.62 (m, 2 H), 2.91 (s, 3 H), 3.00 (dd, J=14.75, 8.65 Hz, 1 H), 3.17 (m, 1 H), 3.27 (s, 2 H), 3.45 (dd, J=14.58, 4.07 Hz, 1 H), 3.79 (m, 1 H), 4.00 (d, J=8.48 Hz, 1 H), 4.10 (m, 1 H), 4.47 (d, J=16.95 Hz, 1 H), 4.62 (d, J=17.29 Hz, 1 H), 7.17 (m, 7 H), 7.76 (d, J=8.82 Hz, 2 H), 7.79 (d, J=6.78 Hz, 2 H), 8.13 (s, 1 H), 8.44 (m, 1 H) Example 459 Η NMR (300 MHz, CDC13) δ ppm 0.78 (dd, J=14.92, 6.78 Hz, 6 H), 0.87 (m, 6 H), 2.93 (s, 3 H), 2.89 (m, 8 H), 3.33 (s, 1 H), 3.50 (s, 3 H), 3.85 (s, 2 H), 4.21 (m, 3 H), 4.57 (d, J=15.94 Hz, 1 H), 4.67 (s, 2 H), 6.68 (d, J=8.82 Hz, 1 H), 7.11 (s, 1 H), 7.20 (dd, J=18.31, 8.14 Hz, 5 H), 7.55 (d, J=8.82 Hz, 1 H), 7.71 (d, J=8.14 Hz, 2 H), 7.82 (d, J=8.48 Hz, 2 H), 8.14 (s, 1 H) Example 460
Η NMR (300 MHz, CD3OD) δ ppm 0.71 (d, J=6.78 Hz, 3 H), 0.79 (t, J=7.46 Hz, 3 H), 0.99 (m, 1 H), 1.14 (m, 1 H), 1.30 (m, 2 H), 1.60 (m, 8 H), 2.24 (m, 1 H), 2.65 (dd, J=13.90, 10.51 Hz, 1 H), 2.95 (s, 3 H), 3.12 (m, 5 H), 3.44 (m, 3 H), 3.46 (m, 1 H), 3.82 (m, 1 H), 4.00 (d, J=8.14 Hz, 1 H), 4.11 (m, 1 H), 4.45 (d, J=16.28 Hz, 1 H), 4.50 (s, 2 H), 4.55 (d, J=16.28 Hz, 1 H), 7.11 (m, 5 H), 7.19 (m, 2 H), 7.37 (d, J=7.80 Hz, 1 H), 7.76 (d, J=7.12 Hz, 2 H), 7.82 (d, J=8.82 Hz, 2 H), 8.13 (s, 1 H) Example 461
Η NMR (300 MHz, DMSO-d6) δ ppm 0.59 (d, J=6.78 Hz, 3 H), 0.69 (t, J=7.46 Hz, 3 H), 0.77 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.92 (m, 1 H), 1.22 (m, 1 H), 1.30 (d, J=6.78 Hz, 6 H), 1.59 (s, 1 H), 1.94 (m, 1 H), 2.56 (m, 1 H), 2.85 (s, 3 H), 2.96 (m, 4 H), 3.21 (dd, J=13.90, 6.78 Hz, 1 H), 3.61 (m, 1 H), 3.94 (t, J=7.97 Hz, 2 H), 4.37 (d, J=16.28 Hz, 1 H), 4.47 (d, J=16.28 Hz, 1 H), 4.97 (d, J=6.44 Hz, 1 H), 5.98 (d, J=8.82 Hz, 1 H), 7.14 (m, 6 H), 7.69 (d, J=9.16 Hz, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.80 (d, J=8.82 Hz, 2 H), 8.23 (s, 1 H) Example 462
Η NMR (300 MHz, DMSO-d6) δ ppm 0.60 (d, J=6.78 Hz, 3 H), 0.69 (t, J=7.29 Hz, 3 H), 0.91 (m, 1 H), 1.07 (m, 1 H), 1.20 (m, 3 H), 1.30 (d, J=6.78 Hz, 6 H), 1.48 (dd, J=17.80, 7.29 Hz, 8 H), 2.19 (m, 1 H), 2.57 (m, 1 H), 2.85 (s, 3 H), 2.97 (m, 1 H), 3.14 (m, 1 H), 3.36 (m, J=3.73 Hz, 1 H), 3.59 (s, 1 H), 3.95 (m, J=7.97, 7.97 Hz, 2 H), 4.37 (d, J=16.28 Hz, 1 H), 4.46 (d, J=16.28 Hz, 1 H), 4.98 (d,J=6.44 Hz, 1 H), 5.98 (d, J=8.48 Hz, 1 H), 7.13 (m, 6 H), 7.69 (d, J=8.82 Hz, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.80 (d, J=8.82 Hz, 2 H), 8.23 (s, 1 H) Example 463 Η NMR (300 MHz, CD3OD) δ ppm 0.69 (d, J=6.78 Hz, 3 H), 0.75 (t, J=7.46 Hz, 3 H), 0.91 (m, 1 H), 1.14 (m, 1 H), 1.29 (m, 2 H), 1.60 (m, 8 H), 2.23 (dd, J=14.92, 7.46 Hz, 1 H), 2.64 (dd, J=13.90, 10.85 Hz, 1 H), 2.99 (s, 3 H), 3.12 (m, 6 H), 3.46 (dd, J=14.58, 3.73 Hz, 1 H), 3.82 (m, 1 H), 3.98 (d, J=8.14 Hz, 1 H), 4.10 (m, 1 H), 4.46 (d, J=16.28 Hz, 1 H), 4.60 (d, J=16.62 Hz, 1 H), 4.79 (s, 2 H), 7.14 (m, 6 H), 7.29 (dd, J=6!78, 2.03 Hz, 1 H), 7.76 (m, 3 H), 7.82 (d, J=8.82 Hz, 2 H), 8.13 (s, 1 H) Example 464
Η NMR (300 MHz, CD3OD) δ ppm 0.86 (s, 9 H), 1.19 (m, 3 H), 1.62 (m, 8 H), 2.23 (m, 1 H), 2.61 (dd, J=13.73, 10.68 Hz, 1 H), 2.96 (s, 3 H), 3.08 (m, 2 H), 3.20 (m, 1 H), 3.43 (s, 3 H), 3.47 (m, 1 H), 3.82 (m, 1 H), 4.03 (s, 1 H), 4.11 (m, 1 H), 4.38 (d, J=16.28 Hz, 1 H), 4.49 (s, 2 H), 4.58 (d, J=16.28 Hz, 1 H), 7.00 (m, 1 H), 7.13 (m, 5 H), 7.37 (d, J=7.80 Hz, 1 H), 7.77 (m, 3 H), 7.81 (d, J=2.37 Hz, 2 H), 8.13 (s, 1 H) Example 465 Η NMR (300 MHz, CDC13) δ ppm 0.91 (s, 9 H), 1.19 (m, 3 H), 1.27 (m, 2 H), 1.29 (s, 9 H), 1.55 (m, 8 H), 2.12 (m, 1 H), 2.87 (m, 1 H), 3.02 (d, J=7.72 Hz, 2 H), 3.08 (m, 1 H), 3.25 (m, 1 H), 3.88 (m, 1 H), 3.94 (d, J=7.72 Hz, 1 H), 4.12 (m, 1 H), 4.33 (d, J=15.81 Hz, 1 H), 4.44 (d, J=15.81 Hz, 1 H), 4.52 (s, 2 H), 6.42 (d, J=8.09 Hz, 1 H), 7.11 (m, 6 H), 7.47 (d, J=7.72 Hz, 1 H), 7.69 (m, 3 H), 7.78 (d, J=8.46 Hz, 2 H), 8.14 (s, 1 H) Example 466 Η NMR (300 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.10 Hz, 3 H), 1.55 (d, J=27.80 Hz, 2 H), 1.70 (d, J=14.92 Hz, 3 H), 1.86 (s, 2 H), 2.62 (m, 1 H), 2.84 (d, J=3.39 Hz, 2 H), 2.86 (s, 3 H), 2.94 (d, J=3.39 Hz, 1 H), 2.99 (d, J=10.17 Hz, 1 H), 3.07 (dd, J=14.07, 6.95 Hz, 1 H), 3.25 (m, 1 H), 3.37 (d, J=3.39 Hz, 3 H), 3.59 (s, 1 H), 3.82 (m, 1 H), 3.89 (s, 1 H), 3.96 (dd, J=7.46, 5.09 Hz, 1 H), 4.48 (s, 2 H), 4.65 (s, 2 H), 5.98 (d, J=7.80 Hz, 1 H), 7.17 (m, 5 H), 7.32 (s, 1 H), 7.61 (d, J=9.16 Hz, 1 H), 7.76 (d, J=8.48 Hz, 2 H), 7.82 (d, J=8.82 Hz, 2 H), 8.23 (s, 1 H) Example 467 Η NMR (300 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.10 Hz, 3 H), 1.06 (d, J=20.01 Hz, 2 H), 1.25 (s, 1 H), 1.44 (d, J=32.89 Hz, 8 H), 2.20 (d, J=7.80 Hz, 1 H), 2.60 (dd, J=13.90, 10.17 Hz, 1 H), 2.86 (s, 3 H), 2.97 (m, 5 H), 3.11 (m, 1 H), 3.62 (s, 1 H), 3.82 (m, 1 H), 3.89 (s, 1 H), 3.97 (dd, J=7.46, 5.43 Hz, 1 H), 4.48 (s, 2 H), 4.65 (s, 2 H), 5.97 (d, J=7.46 Hz, 1 H), 7.16 (m, 5 H), 7.32 (s, 1 H), 7.62 (d, J=9.16 Hz, 1 H), 7.75 (d, J=8.48 Hz, 2 H), 7.81 (d, J=8.82 Hz, 2 H), 8.22 (s, 1 H) Example 468 Η NMR (300 MHz, CD3OD) δ ppm 0.65 (d, J=6\78 Hz, 3 H), 0.74 (t, J=7.29 Hz, 3 H), 0.84 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 1.20 (m, 1 H), 1.59 (s, 1 H), 2.00 (m, 1 H), ' 2.61 (dd, J=14.07, 10.68 Hz, 1 H), 2.88 (s, 3 H), 3.05 (m, 4 H), 3.45 (dd, J=14.75, 3.56 Hz, 1 H), 3.81 (m, 1 H), 4.00 (d, J=7.46 Hz, 1 H), 4.08 (m, 1 H), 4.31 (d, J=16.28 Hz, 1 H), 4.44 (d, J=15.94 Hz, 1 H), 4.79 (s, 3 H), 6.54 (d, J=7.46 Hz, 1 H), 6.61 (m, 2 H), 7.06 (t, J=7.63 Hz, 1 H), 7.16 (m, 5 H), 7.77 (d, J=8.48 Hz, 2 H), 7.83 (d, J=8.82 Hz, 2 H), 8.13 (s, 1 H) Example 469 Η NMR (300 MHz, DMSO-d6) δ ppm 0.76 (d, J=6.78 Hz, 3 H), 0.80 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 1.93 (s, 1 H), 2.61 (s, 3 H), 2.85 (s, 3 H), 2.99 (m, 1 H), 3.38 (m, 1 H), 3.54 (s, 5 H), 3.81 (m, 2 H), 3.97 (m, 1 H), 4.44 (s, 2 H), 6.00 (d, J=6.78 Hz, 1 H), 7.14 (s, 1 H), 7.15 (m, 5 H), 7.61 (d, J=9.16 Hz, 1 H), 7.76 (d, J=8.48 Hz, 2 H), 7.81 (d, J=8.48 Hz, 2 H), 8.23 (s, 1 H) Example 470 Η NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.44 Hz, 3 H), 1.55 (d, J=27.47 Hz, 2 H), 1.70 (m, 3 H), 1.86 (s, 2 H), 2.61 (s, 3 H), 2.85 (s, 3 H), 2.94 (m, 1 H), 3.06 (m, 2 H), 3.27 (m, 5 H), 3.85 (m, 3 H), 4.44 (s, 2 H), 6.01 (d, J=6.78 Hz, 1 H), 7.15 (s, 1 H), 7.17 (m, 5 H), 7.60 (d, J=9.16 Hz, 1 H), 7.76 (d, J=8.48 Hz, 2 H), 7.82 (d, J=8.48 Hz, 2 H), 8.23 (s, 1 H) Example 471
Η NMR (300 MHz, DMSO-d6) δ ppm 0.64 (d, J=6.44 Hz, 3 H), 0.73 (t, J=7.46 Hz, 3 H), 0.78 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.96 (m, 1 H), 1.38 (s, 1 H), 1.60 (s, 1 H), 1.96 (m, 1 H), 2.55 (m, 1 H), 2.82 (d, J=6.78 Hz, 1 H), 2.88 (s, 3 H), 2.98 (m, 2 H), 3.34 (m, 1 H), 3.62 (s, 2 H), 3.91 (s, 1 H), 4.01 (m, 1 H), 4.40 (d, J=16.28 Hz, 3 H), 4.55 (d, J=15.94 Hz, 1 H), 6.14 (d, J=8.48 Hz, 1 H), 7.09 (m, 5 H), 7.42 (s, 1 H), 7.78 (m, 4 H), 7.94 (d, J=9.16 Hz, 1 H), 8.24 (s, 1 H), 8.42 (s, 2 H) Example 472
Η NMR (300 MHz, DMSO-d6) δ ppm 0.65 (d, J=6.44 Hz, 3 H), 0.74 (t, J=7.46 Hz, 3 H), 0.95 (m, J=6.44 Hz, 1 H), 1.24 (d, J=2.71 Hz, 1 H), 1.31 (s, 1 H), 1.68 (m, 4 H), 1.86 (m, 2 H), 2.56 (m, 1 H), 2.88 (s, 3 H), 2.95 (m, 2 H), 3.08 (dd, J=14.07, 6.61 Hz, 1 H), 3.29 (m, 2 H), 3.69 (s, 3 H), 3.90 (s, 1 H), 4.01 (m, 1 H), 4.41 (m, 2 H), 4.55 (d, J=15.94 Hz, 1 H), 6.13 (d, J=8.82 Hz, 1 H), 7.11 (m, 5 H), 7.42 (s, 1 H), 7.79 (m, 4 H), 7.92 (d, J=9.49 Hz, 1 H), 8.24 (s, 1 H), 8.42 (s, 2 H) Example 473
Η NMR (300 MHz, DMSO-d6) δ ppm 0.65 (d, J=6.78 Hz, 3 H), 0.74 (t, J=7.29 Hz, 3 H), 0.95 (d, J=6.78 Hz, 1 H), 1.07 (s, 2 H), 1.19 (m, 2 H), 1.43 (dd, J=10.51, 6.10 Hz, 2 H), 1.53 (m, 6 H), 2.20 (s, 1 H), 2.56 (m, 1 H), 2.88 (s, 3 H), 2.99 (m, 2 H), 3.14 (m, 1 H), 3.34 (m, 1 H), 3.63 (s, 1 H), 4.01 (m, 2 H), 4.37 (m, 2 H), 4.55 (d, J=15.94 Hz, 1 H), 6.13 (d, J=8.48 Hz, 1 H), 7.09 (m, 5 H), 7.42 (s, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.81 (d, J=8.82 Hz, 2 H), 7.94 (d, J=9.16 Hz, 1 H), 8.24 (s, 1 H), 8.42 (s, 2 H) Example 474 Η NMR (300 MHz, DMSO-d6) δ ppm 0.65 (d, J=6.78 Hz, 3 H), 0.74 (t, J=7.46 Hz, 3 H), 0.85 (m, 1 H), 0.98 (dd, J=16.62, 6.44 Hz, 1 H), 1.18 (t, J=7.29 Hz, 4 H), 1.49 (d, J=6.78 Hz, 3 H), 1.48 (m, J=35.26 Hz, 6 H), 2.18 (d, J=7.12 Hz, 1 H), 2.58 (m, 1 H), 2.89 (s, 3 H), 2.97 (s, 2 H), 3.10 (m, 2 H), 3.32 (d, J=3.05 Hz, 1 H), 3.63 (s, 1 H), 3.94 (s, 1 H), 4.02 (t, J=8.31 Hz, 1 H), 4.25 (s, 1 H), 4.41 (d, J=15.94 Hz, 1 H), 4.56 (d, J=16.28 Hz, 1 H), 4.82 (s, 1 H), 6.17 (d, J=8.48 Hz, 1 H), 7.12 (m, 5 H), 7.43 (s, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.79 (d, J=8.82 Hz, 2 H), 7.97 (d, J=9.49 Hz, 1 H), 8.24 (s, 1 H), 8.52 (s, 2 H) Example 475
Η NMR (300 MHz, DMSO-d6) δ ppm 0.65 (d, J=6.44 Hz, 3 H), 0.74 (t, J=7.29 Hz, 3 H), 0.95 (d, J=6.44 Hz, 2 H), 1.17 (s, 1 H), 1.34 (s, 2 H), 1.47 (m, 8 H), 1.57 (d, J=6.78 Hz, 3 H), 2.18 (d, J=6.78 Hz, 1 H), 2.55 (m, 1 H), 2.88 (s, 3 H), 2.98 (m, 2 H), 3.14 (m, 1 H), 3.34 (dd, J=14.24, 3.39 Hz, 1 H), 3.64 (s, 1 H), 4.02 (m, 1 H), 4.40 (d, J=16.28 Hz, 1 H), 4.55 (d, J=16.28 Hz, 1 H), 4.71 (s, 1 H), 6.17 (d, J=8.14 Hz, 1 H), 7.09 (m, 5 H), 7.45 (s, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.81 (d, J=8.82 Hz, 2 H), 7.98 (d, J=9.16 Hz, 1 H), 8.24 (s, 1 H), 8.49 (d,
J=4.41 Hz, 2 H)
Example 476
Η NMR (300 MHz, CD3OD) δ ppm 0.66 (d, J=6.78 Hz, 3 H), 0.74 (t, J=7.29 Hz, 3 H), 0.90 (m, 1 H), 1.15 (d, J=6.10 Hz, 1 H), 1.25 (m, 2 H), 1.59 (m, 8 H), 2.22 (m, 1 H), 2.26 (s, 3 H),
2.63 (dd, J=13.73, 10.68 Hz, 1 H), 3.00 (s, 3 H), 3.11 (m, 5 H), 3.45 (dd, J=14.92, 3.73 Hz, 1
H), 3.81 (m, 1 H), 3.97 (m, 1 H), 4.10 (m, 1 H), 4.48 (d, J=16.62 Hz, 1 H), 4.61 (d, J=16.62
Hz, 1 H), 7.16 (m, 7 H), 7.70 (t, J=7.63 Hz, 1 H), 7.76 (d, J=8.82 Hz, 2 H), 7.82 (d, J=8.48
Hz, 2 H), 8.13 (s, I H) Example 477
Η NMR (300 MHz, DMSO-d6) δ ppm 0.61 (d, J=6.99 Hz, 2 H), 0.70 (t, J=7.35 Hz, 3 H),
0.85 (m, 1 H), 0.94 (m, 1 H), 1.08 (s, 1 H), 1.21 (m, 3 H), 1.44 (d, J=6.99 Hz, 3 H), 1.47 (d,
J=32.72 Hz, 8 H), 1.87 (s, 3 H), 2.19 (m, 1 H), 2.57 (m, 1 H), 2.84 (s, 3 H), 2.97 (m, 2 H),
3.13 (m, 1 H), 3.33 (m, 1 H), 3.60 (s, 2 H), 4.42 (s, 2 H), 5.10 (dd, J=14.89, 7.17 Hz, 1 H), 6.04 (d, J=8.46 Hz, 1 H), 7.15 (s, 1 H), 7.14 (m, 5 H), 7.75 (m, 3 H), 7.80 (d, J=8.82 Hz, 2
H), 8.23 (s, 1 H), 8.58 (d, J=8.09 Hz, 1 H)
Example 480
Η NMR (300 MHz, CDC13) δ ppm 0.86 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.26
(s, 1 H), 1.85 (d, J=7.46 Hz, 2 H), 2.09 (s, 1 H), 2.87 (d, L 6.78 Hz, 1 H), 2.99 (m, 3 H), 3.16 (m, 1 H), 3.63 (d, J=10.51 Hz, 1 H), 3.68 (s, 1 H), 3.78 (dd, J=10.68, 4.58 Hz, 1 H), 3.84 (s, 3
H), 4.84 (d, J=8.14 Hz, 1 H), 5.12 (s, 1 H), 7.26 (m, 5 H), 7.71 (d, J=8.48 Hz, 2 H), 7.78 (d,
J=8.48 Hz, 2 H), 8.16 (s, 1 H)
Example 481
Η NMR (300 MHz, DMSO-d6) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 1.99 (s, 1 H), 2.27 (m, 2 H), 2.60 (dd, J=13.90, 10.17 Hz, 1 H), 2.83 (m, 1 H), 2.97 (m, 4 H),
3.63 (s, 1 H), 3.80 (s, 1 H), 4.25 (dd, J=8.48, 5.43 Hz, 1 H), 5.00 (m, 3 H), 6.83 (s, 1 H), 7.12
(dd, J=8.65, 4.24 Hz, 1 H), 7.21 (m, 5 H), 7.35 (s, 4 H), 7.78 (m, 6 H), 8.23 (s, 1 H)
Example 482
Η NMR (300 MHz, CDC13) δ ppm 0.87 (m, 15 H), 1.86 (m, 1 H), 2.83 (dd, J=13.56, 6.78 Hz, 1 H), 2.91 (dd, J=13.73, 4.58 Hz, 1 H), 3.01 (m, 2 H), 3.11 (s, 1 H), 3.65 (s, 3 H), 3.74
(m, 1 H), 3.86 (m, 1 H), 4.21 (s, 1 H), 5.07 (s, 1 H), 5.99 (d, J=8.48 Hz, 1 H), 7.23 (m, 5 H),
7.56 (s, 1 H), 7.71 (d, J=8.48 Hz, 2 H), 7.77 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H)
Example 483
Η NMR (300 MHz, CD3OD) δ ppm 0.86 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.80 (s, 3 H), 2.01 (m, 1 H), 2.60 (m, 1 H), 2.90 (m, 1 H), 2.97 (m, 1 H), 3.12 (m, 2 H), 3.41 (dd,
J=14.92, 3.05 Hz, 1 H), 3.78 (m, 1 H), 4.01 (m, 1 H), 4.80 (s, 1 H), 7.19 (m, 5 H), 7.79 (m, 4
H), 8.14 (s, l H) Example 484
Η NMR (300 MHz, CDC13) δ ppm 0.54 (d, J=6.44 Hz, 3 H), 0.75 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.96 (d, J=6.44 Hz, 3 H), 1.70 (s, 1 H), 1.92 (s, 1 H), 2.79 (s, 1 H), 2.81 (m, 1 H), 2.97 (m, 2 H), 3.26 (dd, J=14.92, 3.05 Hz, 1 H), 3.95 (d, J=4.41 Hz, 2 H), 4.19 (s, 1 H), 5.30 (m, 2 H), 5.40 (m, 2 H), 5.82 (d, J=8.48 Hz, 1 H), 7.23 (m, 5 H), 7.40 (d, J=7.46 Hz, 1 H), 7.74 (m, 6 H), 8.15 (s, 1 H), 8.57 (d, J=4.75 Hz, 1 H) Example 485
Η NMR (300 MHz, CDC13) δ ppm 0.60 (d, J=6.78 Hz, 3 H), 0.83 (s, 1 H), 0.85 (m, 9 H), 1.26 (s, 1 H), 1.86 (s, 1 H), 2.12 (m, 1 H), 2.92 (d, J=8.14 Hz, 2 H), 3.05 (d, J=4.75 Hz, 1 H), 3.12 (d, J=8.14 Hz, 1 H), 3.19 (m, 1 H), 3.80 (s, 1 H), 3.91 (s, 1 H), 4.12 (s, 1 H), 5.09 (s, 1 H), 5.23 (s, 2 H), 6.28 (s, 1 H), 7.21 (dd, J=13.39, 6.61 Hz, 7 H), 7.30 (m, 1 H), 7.71 (d, L 8.14 Hz, 2 H), 7.78 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H) Example 486 Η NMR (300 MHz, CDC13) δ ppm 0.88 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 2 H), 1.90 (m, 1 H), 2.10 (s, 6 H), 3.02 (m, 1 H), 3.17 (m, 3 H), 3.97 (m, 1 H), 4.09 (d, J=14.92 Hz, 1 H), 4.19 (m, 1 H), 4.28 (m, 1 H), 6.96 (m, 5 H), 7.05 (d, J=8.48 Hz, 1 H), 7.23 (m, 6 H), 7.30 (s, 1 H), 7.71 (d, J=8.48 Hz, 2 H), 7.80 (d, J=8.48 Hz, 2 H), 8.02 (s, 1 H), 8.15 (s, 1 H) Example 487 Η NMR (300 MHz, CDC13) δ ppm 0.61 (d, J=6.78 Hz, 3 H), 0.83 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.78 Hz, 6 H), 1.86 (m, 1 H), 2.10 (d, J=5.76 Hz, 1 H), 2.90 (m, 2 H), 3.04 (m, 1 H), 3.10 (d, J=7.80 Hz, 2 H), 3.15 (d, J=4.07 Hz, 1 H), 3.83 (dd, J=8.31, 3.90 Hz, 1 H), 3.89 (dd, J=8.14, 5.43 Hz, 1 H), 4.19 (m, 1 H), 4.89 (d, J=1.36 Hz, 1 H), 5.07 (s, 2 H), 6.23 (d, J=8.14 Hz, 1 H), 7.20 (m, 5 H), 7.33 (m, 5 H), 7.60 (s, 1 H), 7.71 (d, J=8.48 Hz, 2 H), 7.80 (d, J=8.48 Hz, 2 H), 8.15 (s, I H) Example 488
Η NMR (300 MHz, CDC13) δ ppm 0.89 (t, J=6.44 Hz, 6 H), 1.08 (d, J=6.44 Hz, 3 H), 1.84 (dd, J=14.24, 7.12 Hz, 1 H), 2.80 (dd, J=14.24, 10.17 Hz, 2 H), 2.97 (m, 2 H), 3.11 (m, 5 H), 3.86 (m, 1 H), 3.96 (dd, J=7.80, 1.70 Hz, 1 H), 4.20 (m, J=4.75 Hz, 2 H), 5.10 (s, 2 H), 5.40 (d, J=6.78 Hz, 1 H), 6.60 (d, J=7.80 Hz, 1 H), 7.21 (m, 4 H), 7.34 (m, 5 H), 7.72 (d, J=8.48 Hz, 2 H), 7.80 (d, J=8.48 Hz, 2 H), 8.16 (s, 1 H) Example 489
Η NMR (300 MHz, CDC13) δ ppm 0.87 (dd, J=6.78, 5.09 Hz, 3 H), 0.92 (m, 3 H), 1.65 (s, 2 H), 1.85 (d, J=2.71 Hz, 4 H), 2.11 (m, 3 H), 2.11 (m, 2 H), 3.46 (m, 1 H), 3.85 (m, 6 H), 4.13 (dd, J=10.17, 6.10 Hz, 1 H), 5.04 (m, 1 H), 5.22 (s, 1 H), 7.26 (m, 5 H), 7.74 (m, 4 H), 8.16 (s, 1 H)
Example 490 Η NMR (300 MHz, CDC13) δ ppm 0.84 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.78 Hz, 3 H), 1.81 (s, 1 H), 2.82 (m, 1 H), 2.98 (m, 2 H), 3.15 (m, 1 H), 3.83 (s, 2 H), 4.88 (m, 3 H), 6.32 (s, 1 H), 6.90 (m, 1 H), 7.26 (m, 6 H), 7.37 (m, J=5.43, 5.43 Hz, 1 H), 7.70 (d, J=8.48 Hz, 2 H), 7.76 (d, J=8.82 Hz, 2 H), 8.17 (m, 2 H) Example 491
Η NMR (300 MHz, CDC13) δ ppm 0.87 (dd, J=10.34, 6.61 Hz, 6 H), 1.88 (m, 1 H), 2.95 (m, 6 H), 3.19 (m, 1 H), 3.75 (m, 1 H), 3.88 (s, 1 H), 4.13 (s, 1 H), 5.29 (m, 2 H), 5.71 (s, 1 H), 6.44 (m, 1 H), 7.20 (t, J=7.46 Hz, 4 H), 7.42 (m, 3 H), 7.72 (q, J=8.48 Hz, 4 H), 7.85 (m, 1 H), 8.15 (s, 1 H), 8.61 (d, J=4.75 Hz, 1 H) Example 492
Η NMR (300 MHz, CDC13) δ ppm 0.79 (dd, J=6.10, 3.39 Hz, 6 H), 0.88 (dd, J=6.44, 3.05 Hz, 6 H), 1.42 (s, 9 H), 1.89 (m, 1 H), 2.89 (m, 4 H), 3.09 (m, 5 H), 3.84 (s, 2 H), 4.15 (s, 1 H), 4.61 (s, 1 H), 6.25 (d, J=7.46 Hz, 1 H), 7.26 (m, 5 H), 7.75 (m, 4 H), 8.15 (s, 1 H) Example 493 Η NMR (300 MHz, CDC13) δ ppm 0.77 (t, J=6.95 Hz, 6 H), 0.88 (d, J=6.44 Hz, 6 H), 1.01 (s, 1 H), 1.84 (s, 2 H), 2.90 (s, 4 H), 3.06 (s, 4 H), 3.84 (s, 1 H), 3.93 (s, 1 H), 4.15 (m, 1 H), 4.87 (s, 1 H), 5.07 (s, 2 H), 6.24 (s, 1 H), 7.21 (m, 5 H), 7.36 (m, 5 H), 7.71 (d, J=7.80 Hz, 2 H), 7.80 (m, 2 H), 8.15 (s, I H) Example 494 Η NMR (300 MHz, CDC13) δ ppm 0.88 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.85 (m, 1 H), 2.79 (s, 3 H), 2.87 (m, 2 H), 2.98 (dd, J=12.55, 4.41 Hz, 1 H), 3.07 (m, 1 H), 3.16 (m, 3 H), 3.89 (d, J=7.80 Hz, 2 H), 4.41 (t, J=5.43 Hz, 2 H), 4.95 (s, 1 H), 7.27 (m, 5 H), 7.59 (m, 1 H), 7.72 (d, J=8.48 Hz, 2 H), 7.79 (m, 2 H), 8.17 (s, 1 H) Example 495 Η NMR (300 MHz, CDC13) δ ppm 0.88 (dd, J=6.61, 4.24 Hz, 6 H), 0.92 (d, J=6.78 Hz, 1 H), 1.43 (s, 9 H), 1.86 (m, 1 H), 2.89 (s, 3 H), 2.93 (m, 3 H), 2.99 (m, 1 H), 3.06 (m, 1 H), 3.14 (m, 2 H), 3.88 (m, 1 H), 4.20 (m, 2 H), 5.11 (d, J=8.14 Hz, 1 H), 6.58 (d, J=8.14 Hz, 1 H), 7.25 (m, 5 H), 7.49 (m, 1 H), 7.72 (d, J=8.82 Hz, 2 H), 7.81 (m, 3 H), 8.16 (s, 1 H) Example 496 Η NMR (300 MHz, CDC13) δ ppm 0.88 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.43 (s, 1 H), 1.66 (m, 2 H), 1.86 (d, J=7.12 Hz, 1 H), 2.10 (m, 1 H), 2.85 (m, 2 H), 3.02 (m, 3 H), 3.18 (m, 1 H), 3.42 (m, 1 H), 3.56 (d, J=7.46 Hz, 1 H), 3.86 (m, 3 H), 4.15 (m, 1 H), 4.93 (d, J=8.82 Hz, 1 H), 5.02 (d, J=4.07 Hz, 1 H), 5.21 (dd, J=6.27, 3.22 Hz, 1 H), 7.25 (m, 5 H), 7.67 (s, 1 H), 7.75 (m, 4 H), 8.16 (s, 1 H) Example 497
Η NMR (300 MHz, CDC13) δ ppm 0.86 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.34 (m, 1 H), 1.84 (s, 2 H), 2.17 (s, 1 H), 2.85 (m, 2 H), 2.94 (d, J=5.76 Hz, 2 H), 3.02 (m, 4 H), 3.11 (s, 1 H), 3.46 (m, 1 H), 3.88 (m, 3 H), 4.13 (dd, J=10.17, 6.44 Hz, 1 H), 5.05 (d, J=3.73 Hz, 1 H), 5.21 (s, 1 H), 7.27 (m, 5 H), 7.60 (s, 1 H), 7.74 (m, 4 H), 8.16 (s, 1 H) Example 498
Η NMR (300 MHz, CD3OD) δ ppm 0.83 (d, J=6.78 Hz, 3 H), 0.89 (m, 3 H), 1.99 (d, J=7.12 Hz, 1 H), 2.67 (dd, J=13.90, 10.51 Hz, 1 H), 2.92 (m, 1 H), 2.99 (d, J=9.16 Hz, 1 H), 3.04 (dd, J=8.48, 4.75 Hz, 1 H), 3.12 (dd, J=14.41, 8.31 Hz, 3 H), 3.36 (d, J=5.09 Hz, 1 H), 3.49 (d, J=11.87 Hz, 1 H), 3.83 (m, 1 H), 4.05 (s, 1 H), 4.52 (dd, J=8.31, 4.92 Hz, 1 H), 4.80 (s, 4 H), 5.09 (s, 2 H), 7.14 (dd, J=8.14, 4.07 Hz, 1 H), 7.20 (d, J=4.41 Hz, 4 H), 7.30 (d, J=8.82 Hz, 1 H), 7.34 (m, 3 H), 7.76 (d, J=8.48 Hz, 2 H), 7.83 (m, 2 H), 8.13 (s, 1 H) Example 499
Η NMR (300 MHz, CD3OD) δ ppm 0.83 (d, J=6.78 Hz, 3 H), 0.89 (d, J=6.44 Hz, 3 H), 1.63 (m, 1 H), 1.75 (m, 1 H), 1.99 (s, 3 H), 2.01 (m, 1 H), 2.31 (m, 2 H), 2.66 (dd, J=13.73, 10.68 Hz, 1 H), 2.93 (dd, J=14.24, 7.46 Hz, 2 H), 3.02 (m, 2 H), 3.09 (m, 1 H), 3.16 (dd, J=14.07, 3.90 Hz, 1 H), 3.45 (d, J=16.95 Hz, 1 H), 3.80 (m, 1 H), 4.02 (s, 1 H), 4.10 (m, 1 H), 5.06 (d, J=6.10 Hz, 2 H), 7.14 (m, 1 H), 7.20 (d, J=4.41 Hz, 5 H), 7.31 ( , 4 H), 7.77 (d, J=8.48 Hz, 2 H), 7.84 (d, J=8.48 Hz, 2 H), 8.13 (s, 1 H) Example 500
Η NMR (300 MHz, CD3OD) δ ppm 0.83 (m, 9 H), 0.89 (m, 3 H), 1.25 (m, 2 H),1 1.49 (m, 1 H), 2.01 (s, 1 H), 2.66 (dd, J=13.90, 10.51 Hz, 1 H), 2.93 (dd, J=13.56, 7.12 Hz, 2 H), 2.99 (d, J=9.16 Hz, 1 H), 3.07 (m, 2 H), 3.17 (dd, J=13.73, 3.90 Hz, 1 H), 3.45 (dd, J=15.26, 2.71 Hz, 1 H), 3.79 (m, 1 H), 4.01 (dd, J=9.32, 5.93 Hz, 1 H), 5.05 (m, 2 H), 7.13 (m, 1 H), 7.19 (d, J=4.41 Hz, 5 H), 7.29 (dd, J=8.31, 5.26 Hz, 5 H), 7.76 (d, J=8.14 Hz, 2 H), 7.83 (m, 2 H), 8.13 (s, 1 H) Example 501 Η NMR (300 MHz, CD3OD) δ ppm 0.82 (s, 9 H), 0.84 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 1.98 (m, 1 H), 2.62 (dd, J=13.90, 10.85 Hz, 1 H), 2.95 (dd, J=13.90, 7.12 Hz, 2 H), 3.05 (m, 2 H), 3.13 (m, 1 H), 3.44 (dd, J=14.58, 3.39 Hz, 1 H), 3.78 (m, 1 H), 3.86 (s, 1 H), 4.10 (m, 1 H), 5.07 (s, 2 H), 7.06 (d, J=7.12 Hz, 1 H), 7.13 (t, J=7.29 Hz, 2 H), 7.20 (m, 3 H), 7.32 (m, 5 H), 7.76 (d, J=8.82 Hz, 2 H), 7.82 (d, J=8.48 Hz, 2 H), 8.13 (s, 1 H) Example 502
Η NMR (300 MHz, CD3OD) δ ppm 0.83 (d, J=6.44 Hz, 3 H), 0.89 (m, 3 H), 1.43 (m, 6 H), 1.93 (s, 1 H), 2.59 (t, J=6.95 Hz, 2 H), 2.66 (dd, J=13.90, 10.51 Hz, 1 H), 2.94 (m, 2 H), 3.05 (m, 2 H), 3.15 (m, 1 H), 3.48 (d, J=15.60 Hz, 1 H), 3.79 (m, 1 H), 3.96 (m, 1 H), 4.05 (d, J=7.12 Hz, 1 H), 5.07 (m, 2 H), 7.12 (m, 1 H), 7.19 (m, 5 H), 7.30 (dd, J=8.48, 5.43 Hz, 5 H), 7.76 (d, J=8.48 Hz, 2 H), 7.84 (d, J=8.48 Hz, 2 H), 8.13 (s, 1 H) Example 503 Η NMR (300 MHz, CD3OD) δ ppm 0.83 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 1.97 (m, 1 H), 2.64 (dd, J=15.09, 9.32 Hz, 1 H), 2.71 (d, J=10.17 Hz, 1 H), 2.84 (m, 2 H), 2.94 (m, 1 H), 3.02 (dd, J=8.65, 6.61 Hz, 2 H), 3.11 (m, 1 H), 3.38 (dd, J=15.09, 2.88 Hz, 1 H), 3.79 (m, 1 H), 4.04 (m, 1 H), 4.25 (dd, J=9.16, 5.09 Hz, 1 H), 5.02 (m, 2 H), 6.74 (s, 1 H), 7.12 (m, 1 H), 7.19 (m, 7 H), 7.29 (m, 6 H), 7.55 (s, 1 H), 7.74 (d, J=8.14 Hz, 2 H), 7.82 (m, 2 H), 8.11 (s, l H) Example 504
Η NMR (300 MHz, CD3OD) δ ppm 0.82 (d, J=6.44 Hz, 3 H), 0.85 (d, J=6.44 Hz, 3 H), 1.92 (m, 1 H), 2.01 (s, 1 H), 2.65 (dd, J=13.90, 9.83 Hz, 1 H), 2.80 (d, J=14.58 Hz, 1 H), 2.85 (m, 1 H), 2.91 (m, 2 H), 2.98 (m, 2 H), 3.08 (m, 2 H), 3.71 (d, J=9.83 Hz, 1 H), 3.99 (s, 1 H), 4.32 (m, 1 H), 4.97 (d, J=7.12 Hz, 2 H), 6.95 (s, 1 H), 6.98 (d, J=7.12 Hz, 1 H), 7.07 (m, 2 H), 7.16 (m, 6 H), 7.26 (m, 6 H), 7.54 (d, J=7.80 Hz, 1 H), 7.73 (d, J=8.48 Hz, 2 H), 7.80 (m, 2 H), 8.09 (s, 1 H) Example 505 Η NMR (300 MHz, CD3OD) δ ppm 0.82 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 1.05 (d, J=6.10 Hz, 3 H), 1.97 (d, J=14.24 Hz, 1 H), 2.70 (dd, J=13.90, 10.17 Hz, 1 H), 2.91 (dd, J=13.73, 6.95 Hz, 2 H), 2.99 (d, J=9.16 Hz, 1 H), 3.04 (m, 2 H), 3.12 (m, 2 H), 3.44 (dd, J=14.92, 3.05 Hz, 1 H), 3.68 (d, J=15.60 Hz, 1 H), 3.79 (m, 2 H), 3.89 (d, J=15.60 Hz, 1 H), 4.10 (m, 2 H), 5.11 (m, 2 H), 7.12 (m, 1 H), 7.19 (m, 5 H), 7.31 (m, 5 H), 7.79 (m, 4 H), 8.13 (s, 1 H)
Example 506
Η NMR (300 MHz, CD3OD) δ ppm 0.84 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.44 Hz, 3 H), 2.01 (s, 2 H), 2.44 (dd, J=16.78, 7.97 Hz, 1 H), 2.93 (dd, J=14.41, 7.29 Hz, 2 H), 3.04 (m, 3 H), 3.14 (m, 1 H), 3.40 (d, J=2.71 Hz, 1 H), 3.57 (s, 3 H), 3.79 (m, 1 H), 3.98 (s, 1 H), 4.40 (t, J=6.95 Hz, 1 H), 5.09 (m, 2 H), 7.13 (m, 1 H), 7.19 (m, 5 H), 7.32 (m, 5 H), 7.80 (m, 4 H), 8.13 (s, 1 H) Example 507
Η NMR (300 MHz, CD3OD) δ ppm 0.70 (d, J=6.78 Hz, 3 H), 0.77 (t, J=7.46 Hz, 3 H), 1.03 (m, 2 H), 1.24 (m, 2 H), 1.57 (m, 8 H), 2.22 (dd, J=14.92, 7.46 Hz, 1 H), 2.66 (dd, J=13.90, 10.85 Hz, 1 H), 3.02 (d, J=7.12 Hz, 1 H), 3.08 (m, 1 H), 3.18 (m, 3 H), 3.45 (dd, J=14.92, 3.73 Hz, 1 H), 3.80 (dd, J=6.44, 3.39 Hz, 1 H), 3.85 (m, 1 H), 4.12 (m, 1 H), 5.16 (s, 2 H), 7.09 (m, 1 H), 7.20 (m, 5 H), 7.33 (dd, J=6.95, 5.59 Hz, 1 H), 7.45 (d, J=7.80 Hz, 1 H), 7.79 (m, 4 H), 8.13 (s, 1 H), 8.50 (d, J=4.07 Hz, 1 H) Example 508 Η NMR (300 MHz, CD3OD) δ ppm 0.70 (d, J=6.78 Hz, 3 H), 0.77 (t, J=7.46 Hz, 3 H), 0.98 (m, 1 H), 1.12 (m, 1 H), 1.24 (m, 2 H), 1.58 (m, 8 H), 2.23 (m, 1 H), 2.66 (dd, J=13.90, 10.85 Hz, 1 H), 3.05 (m, 2 H), 3.19 (m, 2 H), 3.44 (s, 3 H), 3.45 (m, 1 H), 3.81 (m, 1 H), 3.85 (d, J=7.12 Hz, 1 H), 4.11 (m, 1 H), 4.52 (s, 2 H), 5.14 (s, 2 H), 7.09 (m, 1 H), 7.20 (m, 5 H), 7.36 (dd, J=15.60, 7.80 Hz, 2 H), 7.79 (m, 5 H), 8.12 (s, 1 H) Example 509
Η NMR (300 MHz, CD3OD) δ ppm 0.84 (s, 9 H), 1.15 (s, 1 H), 1.23 (s, 1 H), 1.56 (d, J=3.68 Hz, 8 H), 2.22 (dd, J=14.71, 6.99 Hz, 1 H), 2.65 (dd, J=13.79, 10.48 Hz, 1 H), 3.06 (m, 1 H), 3.15 (m, 1 H), 3.44 (s, 3 H), 3.46 (m, 3 H), 3.82 (m, 1 H), 3.87 (s, 1 H), 4.14 (m, 1 H), 4.53 (s, 2 H), 5.15 (s, 2 H), 7.07 (d, J=6.62 Hz, 1 H), 7.18 (m, 5 H), 7.37 (dd, J=16.73, 7.91 Hz, 2 H), 7.79 (m, 5 H), 8.13 (s, I H) Example 510 Η NMR (300 MHz, CDC13) δ ppm 0.85 (d, J=6.62 Hz,.3 H), 0.89 (d, J=6.62 Hz, 3 H), 1.80 (m, 1 H), 2.84 (dd, J=13.24, 6.99 Hz, 1 H), 2.96 (m, 2 H), 3.05 (d, J=5.15 Hz, 2 H), 3.14 (m, 1 H), 3.85 (s, 2 H), 4.93 (d, J=7.35 Hz, 1 H), 5.02 (s, 2 H), 7.20 (d, J=8.09 Hz, 4 H), 7.27 (m, 3 H), 7.55 (s, 1 H), 7.73 (q, J=8.58 Hz, 4 H), 8.17 (s, 1 H), 8.56 (dd, J=4.96, 1.65 Hz, 1 H) Example 511 Η NMR (300 MHz, CDC13) δ ppm 0.86 (d, J=6.62 Hz, 3 H), 0.90 (d, J=6.62 Hz, 3 H), 1.82 (d, J=7.72 Hz, 1 H), 2.84 (dd, J=13.60, 6.99 Hz, 1 H), 2.97 (m, 1 H), 3.06 (m, 2 H), 3.17 (m, 1 H), 3.64 (s, 1 H), 3.89 (s, 2 H), 5.02 (d, J=3.31 Hz, 2 H), 7.07 (d, J=4.41 Hz, 2 H), 7.28 (m, 5 H), 7.70 (d, J=8.46 Hz, 2 H), 7.77 (m, 2 H), 8.13 (s, 1 H), 8.16 (s, 1 H), 8.54 (d, J=5.88 Hz, 2 H) Example 512
Η NMR (300 MHz, CDC13) δ ppm 0.85 (m, 3 H), 0.90 (m, 3 H), 1.86 (m, 1 H), 2.82 (m, 1 H), 2.98 (m, 2 H), 3.15 (m, 1 H), 3.62 (s, 1 H), 3.85 (s, 2 H), 4.88 (s, 1 H), 5.20 (m, 2 H), 6.90 (m, 1 H), 7.24 (m, 6 H), 7.76 (m, 5 H), 8.17 (m, 2 H), 8.78 (m, 1 H) Example 513 Η NMR (300 MHz, CD3OD) δ ppm 0.85 (d, J=7.46 Hz, 12 H), 0.89 (d, J=6.78 Hz, 3 H),
1.98 (m, 1 H), 2.59 (m, 1 H), 2.97 (m, 1 H), 3.04 (m, 2 H), 3.12 (m, 2 H), 3.20 (m, 3 H), 3.45 (dd, J=14.92, 3.39 Hz, 1 H), 3.63 (s, 3 H), 3.78 (m, 1 H), 4.09 (m, 1 H), 4.14 (s, 1 H), 7.03 (m, 2 H), 7.18 (m, 6 H), 7.31 (m, 1 H), 7.76 (m, 2 H), 7.82 (d, J=8.82 Hz, 2 H), 8.14 (s, 1 H) Example 514 Η NMR (300 MHz, CD3OD) δ ppm 0.63 (s, 9 H), 0.81 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.78 Hz, 3 H), 1.97 (m, 1 H), 2.59 (dd, J=14.58, 11.53 Hz, 1 H), 2.89 (m, 1 H), 3.06 (m, 2 H), 3.21 (d, J=4.07 Hz, 4 H), 3.26 (d, J=4.07 Hz, 1 H), 3.43 (m, 1 H), 3.63 (s, 2 H), 3.72 (m, 1 H), 4.08 (s, 1 H), 4.17'(m, 1 H), 6.95 (m, 1 H), 7.12 (m, 2 H), 7.23 (m, 6 H), 7.31 (m, 1 H), 7.74 (m, 2 H), 7.79 (m, 2 H), 8.12 (s, 1 H) Example 515
Η NMR (300 MHz, CD3OD) δ ppm 0.73 (d, J=6.78 Hz, 3 H), 0.80 (m, 3 H), 0.83 (m, 3 H), 0.90 (t, J=5.93 Hz, 3 H), 1.00 (m, 1 H), 1.69 (m, 1 H), 1.97 (m, J=6.78 Hz, 1 H), 2.64 (m, 1 H), 2.94 (m, 2 H), 3.02 (d, J=5.76 Hz, 1 H), 3.07 (m, 2 H), 3.17 (m, 2 H), 3.45 (m, 1 H), 3.76 (m, 1 H), 3.92 (m, 1 H), 4.09 (m, 4 H), 7.15 (m, 1 H), 7.22 (m, 5 H), 7.80 (m, 4 H), 8.14 (s, 1
H)
Example 516 Η NMR (300 MHz, CD3OD) δ ppm 0.73 (d, J=6.78 Hz, 3 H), 0.78 (m, 3 H), 0.83 (m, 3 H), 0.89 (d, J=6.78 Hz, 3 H), 0.97 (m, 1 H), 1.26 (m, 1 H), 1.64 (d, J=6.78 Hz, 1 H), 2.00 (m, 1 H), 2.62 (m, 1 H), 2.94 (m, 1 H), 3.03 (m, 1 H), 3.08 (m, 1 H), 3.13 (d, J=4.41 Hz, 1 H), 3.20 (m, 4 H), 3.45 (m, 1 H), 3.66 (m, 2 H), 3.78 (m, 1 H), 4.09 (m, 1 H), 4.13 (m, 1 H), 6.98 (m, 1 H), 7.09 (m, 3 H), 7.12 (m, 1 H), 7.18 (d, J=6.78 Hz, 3 H), 7.23 (t, J=3.90 Hz, 1 H), 7.31 (m, 1 H), 7.76 (m, 2 H), 7.83 (m, 2 H), 8.13 (s, 1 H) Example 517
Η NMR (300 MHz, CD3OD) δ ppm 0.74 (d, J=6.78 Hz, 3 H), 0.77 (d, J=7.12 Hz, 3 H), 0.84 (m, 3 H), 0.89 (d, J=6.44 Hz, 3 H), 1.28 (s, 1 H), 1.67 (d, J=9.83 Hz, 1 H), 2.02 (d, J=5.76 Hz, 1 H), 2.62 (dd, J=13.90, 10.85 Hz, 1 H), 2.97 (m, 2 H), 3.07 (m, 1 H), 3.14 (m, 1 H), 3.21 (d, J=2.71 Hz, 2 H), 3.25 (s, 2 H), 3.47 (m, 1 H), 3.64 (m, 2 H), 3.79 (d, J=3.39 Hz, 1 H), 4.08 (m, 1 H), 4.13 (d, J=7.12 Hz, 1 H), 7.10 (m, 1 H), 7.20 (m, 5 H), 7.60 (d, J=1.70 Hz, 1 H), 7.72 (d, J=8.48 Hz, 1 H), 7.80 (m, 4 H), 7.96 (d, J=2.03 Hz, 1 H), 8.13 (s, 1 H) Example 518 Η NMR (300 MHz, CD3OD) δ ppm 0.82 (d, J=,6.44 Hz, 3 H), 0.89 (d, J=6.78 Hz, 3 H), 1.36 (m, 2 H), 1.47 (m, 2 H), 1.95 (s, 1 H), 2.64 (dd, J=13.90, 10.51 Hz, 1 H), 2.94 (m, 2 H), 3.05 (m, 5 H), 3.16 (m, 2 H), 3.49 (s, 1 H), 3.78 (m, 1 H), 3.98 (t, J=7.12 Hz, 1 H), 4.08 (s, 1 H), 5.08 (m, 2 H), 7.14 (m, 1 H), 7.19 (m, 5 H), 7.30 (dd, J=7.97, 4.92 Hz, 5 H), 7.81 (m, 4 H), 8.14 (s, l H) Example 519 Η NMR (300 MHz, CDC13) δ ppm 0.80 (d, J=6.62 Hz, 3 H), 0.86 (s, 3 H), 0.95 (s, 9 H), 1.81 (dd, J=14.89, 8.27 Hz, 4 H), 2.80 (dd, J=13.05, 6.43 Hz, 1 H), 2.95 (d, J=5.15 Hz, 2 H), 3.04 (d, J=12.87 Hz, 1 H), 3.25 (s, 1 H), 3.74 (s, 1 H), 4.00 (s, 1 H), 4.36 (s, 1 H), 7.22 (m, 5 H), 7.40 (s, 1 H), 7.66 (d, J=8.46 Hz, 2 H), 7.74 (d, J=8.82 Hz, 2 H), 8.16 (s, 1 H) Example 520 Η NMR (300 MHz, CD3OD) δ ppm 0.80 (d, J=6.62 Hz, 3 H), 0.89 (d, J=6.62 Hz, 3 H), 1.95 (m, 1 H), 2.53 (dd, J=13.97, 9.93 Hz, 1 H), 2.90 (m, 3 H), 2.98 (dd, J=9.93, 4.04 Hz, 1 H), 3.07 (m, 1 H), 3.56 (m, 2 H), 3.88 (m, 1 H), 7.01 (s, 5 H), 7.47 (m, 4 H), 7.78 (m, 4 H), 8.08 (s, 1 H), 8.15 (s, 1 H) Example 525 Η NMR (300 MHz, DMSO-d6) δ ppm 0.67 (d, J=6.44 Hz, 3 H), 0.70 (d, J=6.78 Hz, 3 H), 0.81 (dd, J=6.61, 3.22 Hz, 6 H), 1.94 (m, 2 H), 2.42 (dd, J=13.39, 11.02 Hz, 1 H), 2.59 (m, 1 H), 2.63 (s, 3 H), 2.80 (dd, J=13.73, 6.61 Hz, 1 H), 2.90 (m, 1 H), 3.00 (m, 2 H), 3.19 (m, 2 H), 3.59 (s, 1 H), 3.75 (d, J=10.85 Hz, 1 H), 3.83 (s, 3 H), 3.89 (d, J=10.17 Hz, 1 H), 4.33 (s, 2 H), 4.93 (d, J=6.44 Hz, 1 H), 7.07 (m, 7 H), 7.22 (s, 1 H), 7.72 (d, J=8.82 Hz, 2 H), 7.87 (d, J=9.49 Hz, 1 H) Example 526 Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 1.51 (s, 1 H), 2.13 (m, 1 H), 2.68 (t, J=4.41 Hz, 1 H), 2.78 (m, 1 H), 2.83 (s, 1 H), 2.98 (m, 2 H), 3.06 (m, 2 H), 3.16 (m, 2 H), 3.33 (dd, J=3.90, 2.20 Hz, 1 H), 3.66 (d, J=10.85 Hz, 1 H), 3.76 (m, 1 H), 3.86 (m, 1 H), 3.87 (s, 2 H), 4.17 (m, 1 H), 4.25 (d, J=14.92 Hz, 1 H), 4.42 (m, 2 H), 6.40 (d, J=8.82 Hz, 1 H), 6.99 (m, 3 H), 7.16 (m, 5 H), 7.29 (m, 1 H), 7.73 (d, J=8.82 Hz, 2 H) Example 527
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.37 (t, J=7.63 Hz, 3 H), 1.54 (s, 1 H), 1.85 (m, 1 H), 2.13 (m, 1 H), 2.28 (t, J=5.76 Hz, 1 H), 2.68 (m, 1 H), 2.80 (m, 1 H), 3.01 (m, 2 H), 3.12 (m, 2 H), 3.20 (m, 2 H), 3.30 (m, 1 H), 3.65 (m, 2 H), 3.75 (m, 1 H), 3.87 (d, J=6.44 Hz, 1 H), 3.87 (s, 3 H), 4.17 (m, 1 H), 4.39 (d, J=14.92 Hz, 1 H), 4.46 (d, J=16.28 Hz, 1 H), 6.42 (d, J=8.82 Hz, 1 H), 6.97 (m, 4 H), 7.16 (m, 3 H), 7.73 (d, J=8.82 Hz, 2 H) Example 528 Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.83 (s, 1 H), 2.04 (s, 3 H), 2.70 (m, 1 H), 2.80 (m, 1 H), 2.99 (m, 2 H), 3.11 (m, 2 H), 3.19 (m, 3 H), 3.48 (s, 2 H), 3.65 (d, J=10.85 Hz, 1 H), 3.76 (s, 1 H), 3.87 (s, 3 H), 4.17 (m, 1 H), 4.39 (d, J=15.60 Hz, 1 H), 4.49 (d, J=15.60 Hz, 1 H), 4.70 (s, 2 H), 6.44 (d, J=9.16 Hz, 1 H), 6.99 (d, J=8.82 Hz, 2 H), 7.10 (s, 1 H), 7.16 (m,> 5 H), 7.72 (d, J=8.82 Hz, 2 H) Example 529
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.83 (m, 1 H), 2.15 (m, 1 H), 2.73 (m, 1 H), 2.80 (m, 1 H), 2.99 (m, 2 H), 3.13 (m, 3 H), 3.22 (m, 1 H), 3.67 (d, J=10.85 Hz, 1 H), 3.77 (m, 1 H), 3.87 (s, 3 H), 4.20 (m, 1 H), 4.58 (d, J=15.94 Hz, 1 H), 4.73 (d, J=15.94 Hz, 1 H), 6.38 (d, J=9.16 Hz, 1 H), 6.96 (s, 1 H), 6.99 (s, 1 H), 7.17 (d, J=3.39 Hz, 1 H), 7.21 (m, 5 H), 7.31 (d, J=3.39 Hz, 1 H), 7.71 (m, 2 H), 7.74 (d, J=1.70 Hz, 2 H) Example 530
Η NMR (300 MHz, CDC13) δ ppm 0.78 (m, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.12 (s, 1 H), 2.28 (s, 3 H), 2.29 (s, 3 H), 2.71 (m, 1 H), 2.78 (m, 1 H), 2.97 (m, 2 H), 3.03 (d, J=2.71 Hz, 2 H), 3.07 (d, J=5.43 Hz, 3 H), 3.12 (d, J=3.05 Hz, 2 H), 3.16 (m, 1 H), 3.67 (d, J=10.85 Hz, 1 H), 3.77 (s, 1 H), 3.87 (s, 3 H), 4.12 (d, J=14.92 Hz, 1 H), 4.19 (m, 1 H), 4.33 (d, J=15.26 Hz, 1 H), 6.46 (d, J=8.82 Hz, 1 H), 6.97 (d, J=8.82 Hz, 1 H), 7.19 (m, 5 H), 7.40 (m, 4 H), 7.71 (s, 1 H), 7.74 (s, 1 H) Example 531
Η NMR (300 MHz, CDC13) δ ppm 0.78 (t, J=6.95 Hz, 6 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 1.31 (t, J=7.46 Hz, 3 H), 1.83 (m, 1 H), 2.10 (m, 1 H), 2.65 (m, 1 H), 2.78 (m, 1 H), 2.93 (m, 4 H), 3.03 (m, 1 H), 3.16 (m, 1 H), 3.27 (m, 1 H), 3.65 (m, 1 H), 3.74 (m, 1 H), 3.87 (s, 3 H), 4.17 (m, 1 H), 4.44 (q, J=14.69 Hz, 2 H), 6.36 (d, J=8.82 Hz, 1 H), 6.98 (m, 2 H), 7.10 (m, 2 H), 7.18 (m, 5 H), 7.40 (m, 4 H), 7.72 (m, 2 H), 7.87 (m, 2 H) Example 532 Η NMR (300 MHz, CDC13) δ ppm 0.77 (t, J=6.61 Hz, 6 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (m, 3 H), 1.23 (t, J=7.63 Hz, 3 H), 1.83 (m, 1 H), 2.11 (m, 1 H), 2.62 (s, 3 H), 2.68 (m, 1 H), 2.78 (dd, J=12.55, 5.76 Hz, 1 H), 2.85 (m, 2 H), 2.96 (m, 2 H), 3.04 (m, 1 H), 3.16 (m, 5 H), 3.64 (d, J=11.19 Hz, 1 H), 3.74 (m, 1 H), 3.87 (s, 3 H), 4.14 (m, 1 H), 4.35 (m, 2 H), 6.37 (d, J=9.16 Hz, 1 H), 6.98 (m, 2 H), 7.16 (m, 5 H), 7.72 (m, 2 H) Example 533
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.78 Hz, 3 H), 0.79 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 1.83 (m, 1 H), 2.10 (m, 1 H), 2.41 (s, 3 H), 2.60 (s, 3 H), 2.67 (m, 1 H), 2.78 (m, 1 H), 2.96 (dd, J=13.39, 8.65 Hz, 1 H), 3.06 (m, 1 H), 3.16 (m, 6 H), 3.63 (d, J=10.85 Hz, 1 H), 3.73 (m, 1 H), 3.87 (s, 3 H), 4.15 (m, 1 H), 4.34 (d, J=3.39 Hz, 2 H), 6.38 (d, J=9.16 Hz, 1 H), 6.97 (m, 2 H), 7.14 (m, 5 H), 7.72 (m, 2 H) Example 534
Η NMR (300 MHz, CDC13) δ ppm 0.81 (m, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 1.84 (m, 1 H), 2.16 (dd, J=17.63, 6.78 Hz, 1 H), 2.78 (m, 3 H), 2.94 (d, J=8.48 Hz, 1 H), 3.01 (m, 2 H), 3.12 (m, 4 H), 3.67 (d, J=10.85 Hz, 1 H), 3.79 (s, 1 H), 3.87 (s, 3 H), 4.15 (d, J=15.60 Hz, 1 H), 4.20 (s, 1 H), 4.41 (d, J=15.94 Hz, 1 H), 6.40 (d, J=8.82 Hz, 1 H),
6.98 (d, J=9.16 Hz, 2 H), 7.19 (m, 5 H), 7.33 (d, J=1.70 Hz, 1 H), 7.73 (d, J=8.82 Hz, 2 H), 7.80 (d, J=1.70 Hz, I H)
Example 535
Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.44 Hz, 6 H), 0.87 (d, L 6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.55 (m, 1 H), 1.84 (m, 1 H), 2.12 (m, 1 H), 2.67 (m, 1 H), 2.79 (m, 1 H),
2.99 (m, 2 H), 3.12 (m, 1 H), 3.72 (d, J=10.85 Hz, 1 H), 3.78 (m, 1 H), 3.85 (d, J=3.05 Hz, 1 H), 3.87 (s, 3 H), 4.18 (m, 1 H), 4.53 (d, J=14.92 Hz, 2 H), 4.64 (d, J=14.58 Hz, 2 H), 6.39 (d, J=9.16 Hz, 2 H), 6.98 (d, J=8.82 Hz, 2 H), 7.11 (m, 5 H), 7.30 (s, 1 H), 7.37 (m, 2 H), 7.74 (d, J=8.82 Hz, 2 H), 7.86 (m, 1 H), 7.92 (m, 1 H) Example 536
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=3.73 Hz, 3 H), 0.81 (d, J=3.39 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.83 (m, 1 H), 2.15 (m, 1 H), 2.73 (m, 1 H), 2.79 (m, 1 H), 2.97 (m, 1 H), 3.06 (m, 3 H), 3.17 (m, 4 H), 3.67 (d, J=10.85 Hz, 1 H), 3.80 (s, 3 H), 3.87 (s, 3 H), 3.90 (m, J=2.71 Hz, 1 H), 4.20 (m, 1 H), 4.51 (d, J=15.26 Hz, 1 H), 4.76 (d, J=15.26 Hz, 1 H), 6.36 (d, J=8.82 Hz, 1 H), 6.98 (d, J=9.16 Hz, 2 H), 7.16 (m, 5 H), 7.32 (m, 4 H), 7.72 (d, J=9.16 Hz, 2 H) Example 537
Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.78 Hz, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 1.83 (m, 1 H), 2.15 (m, 1 H), 2.77 (m, 4 H), 2.97 (m, 3 H), 3.04 (m, 3 H),
3.12 (m, 2 H), 3.70 (s, 3 H), 3.78 (m, 1 H), 3.87 (s, 3 H), 4.19 (m, 1 H), 4.36 (d, J=15.26 Hz,
1 H), 4.65 (d, J=15.26 Hz, 1 H), 6.41 (d, J=7.12 Hz, 1 H), 6.98 (d, J=9.16 Hz, 2 H), 7.15 (m, 9 H), 7.57 (d, J=7.80 Hz, 1 H), 7.72 (d, J=9.16 Hz, 1 H)
Example 538
Η NMR (300 MHz, CDC13) δ ppm 0.80 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.44 Hz, 6 H), 0.92
(d, J=6.78 Hz, 3 H), 1.83 (dd, J=14.58, 6.78 Hz, 1 H), 2.17 (m, 1 H), 2.77 (m, 3 H), 3.00 (m,
2 H), 3.16 (m, 5 H), 3.71 (d, J=10.85 Hz, 1 H), 3.78 (m, 1 H), 3.87 (s, 3 H), 3.89 (d, J=3.05 Hz, 1 H), 4.20 (m, 1 H), 4.53 (d, J=15.26 Hz, 1 H), 4.77 (d, J=15.26 Hz, 1 H), 6.45 (d, J=8.82
Hz, 1 H), 6.98 (d, J=9.16 Hz, 2 H), 7.18 (m, 5 H), 7.38 (d, J=8.48 Hz, 1 H), 7.53 (m, 1 H), 7.73 (d, J=8.82 Hz, 2 H), 7.80 (d, J=8.14 Hz, 1 H), 8.05 (d, J=8.82 Hz, 1 H), 8.14 (d, J=8.48 Hz, I H) Example 539 Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 1.70 (m, 2 H), 1.83 (m, 1 H), 1.94 (m, 3 H),
2.13 (m, 1 H), 2.29 (m, 1 H), 2.69 (m, 2 H), 2.80 (m, 2 H), 3.00 (m, 2 H), 3.11 (m, 2 H), 3.19 (m, 1 H), 3.49 (m, 1 H), 3.64 (d, J=10.85 Hz, 1 H), 3.73 (d, J=11.87 Hz, 1 H), 3.87 (s, 3 H), 4.17 (m, 1 H), 4.38 (t, J=15.26 Hz, 2 H), 6.41 (d, J=9.16 Hz, 1 H), 6.83 (s, 1 H), 6.98 (d, J=8.82 Hz, 2 H), 7.16 (m, 5 H), 7.72 (d, J=8.82 Hz, 1 H) Example 540
Η NMR (300 MHz, CDC13) δ ppm 0.81 (t, J=6.95 Hz, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.17 (m, 1 H), 2.75 (m, 2 H), 2.86 (m, 2 H), 2.96 (m, 1 H), 3.13 (m, 7 H), 3.25 (m, 1 H), 3.29 (m, 2 H), 3.64 (d, J=10.85 Hz, 1 H), 3.79 (m, 1 H), 3.87 (s, 3 H), 4.20 (m, 1 H), 4.39 (d, J=15.94 Hz, 1 H), 6.98 (d, J=9.16 Hz, 2 H), 7.20 (m, 5 H), 7.50 (s, 1 H), 7.72 (d, J=9.16 Hz, 2 H) Example 541
Η NMR (300 MHz, CDC13) δ ppm 0.80 (t, J=6.78 Hz, 6 H), 0.87 (m, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 1.25 (dd, J=6.95, 1.87 Hz, 6 H), 1.84 (m, 1 H), 2.12 (m, 1 H), 2.76 (m, 2 H), 2.98 (m, 2 H), 3.19 (m, 6 H), 3.67 (d, J=10.85 Hz, 1 H), 3.78 (m, 2 H), 3.87 (s, 3 H), 4.19 (m, 1 H), 4.42 (d, J=15.60 Hz, 1 H), 4.61 (d, J=15.60 Hz, 1 H), 6.43 (d, J=9.16 Hz, 1 H), 6.98 (d, J=8.82 Hz, 2 H), 7.16 (m, 5 H), 7.43 (s, 1 H), 7.73 (d, J=8.82 Hz, 2 H) Example 542
Η NMR (300 MHz, CDC13) δ ppm 0.80 (dd, J=9.32, 6.61 Hz, 6 H), 0.86 (d, J=6.44 Hz, 3 H),
0.92 (d, J=6.44 Hz, 3 H), 1.00 (m, 3 H), 1.80 (m, 3 H), 2.13 (m, 2 H), 2.76 (m, 4 H), 2.98 (m,
2 H), 3.19 (m, 5 H), 3.67 (d, J=11.19 Hz, 1 H), 3.78 (m, 1 H), 3.87 (s, 3 H), 4.18 (m, 1 H), 4.42 (d, J=15.60 Hz, 1 H), 4.60 (m, 1 H), 6.49 (d, J=8.82 Hz, 1 H), 6.98 (d, J=8.82 Hz, 2 H), 7.16 (m, 5 H), 7.43 (s, 1 H), 7.73 (d, J=9.16 Hz, 2 H) Example 543
Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=4.78 Hz, 3 H), 0.82 (d, J=4.78 Hz, 3 H), 0.87 (d, J=6.62 Hz, 3 H), 0.92 (d, J=6.62 Hz, 3 H), 1.84 (m, 1 H), 2.16 (s, 1 H), 2.75 (m, 1 H), 2.82 (d, J=9.19 Hz, 2 H), 2.94 (d, J=8.09 Hz, 1 H), 3.04 (d, J=3.31 Hz, 2 H), 3.16 (m, 4 H), 3.68 (d, J=10.66 Hz, 1 H), 3.81 (s, 1 H), 3.87 (s, 3 H), 4.23 (s, 1 H), 4.33 (d, J=15.81 Hz, 1 H), 4.61 (d, J=15.81 Hz, 1 H), 6.42 (s, 1 H), 6.90 (m, 1 H), 6.98 (m, 2 H), 7.19 (m, 5 H), 7.48 (m, 1 H), 7.72 (m, 2 H), 7.79 (d, J=4.04 Hz, 1 H) Example 544 Η NMR (300 MHz, CDC13) δ ppm 0.81 (t, J=6.95 Hz, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.17 (m, 1 H), 2.75 (m, 1 H), 2.93 (m, 3 H), 3.13 (m, 5 H), 3.30 (m, 1 H), 3.64 (d, J=10.85 Hz, 1 H), 3.79 (m, 1 H), 3.87 (s, 3 H), 4.20 (m, 1 H), 4.39 (d, J=15.94 Hz, 1 H), 4.57 (d, J=16.28 Hz, 1 H), 6.44 (d, J=8.82 Hz, 1 H), 6.98 (d, J=9.16 Hz, 2 H), 7.19 (m, 5 H), 7.50 (s, 1 H), 7.72 (d, J=9.16 Hz, 2 H) Example 545
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.13 (m, 1 H), 2.75 (m, 2 H), 2.97 (m, 2 H), 3.12 (m, 4 H), 3.21 (m, 3 H), 3.65 (d, J=10.85 Hz, 1 H), 3.76 (m, 1 H), 3.87 (s,
3 H), 4.18 (m, 1 H), 4.38 (d, J=15.60 Hz, 1 H), 4.51 (d, J=16.28 Hz, 1 H), 4.62 (s, 2 H), 6.45 (d, J=9.16 Hz, 1 H), 6.98 (d, J=9.16 Hz, 2 H), 7.14 (s, 1 H), 7.19 (m, 5 H), 7.72 (d, J=8.82
Hz, 2 H)
Example 546
Η NMR (300 MHz, CDC13) δ ppm 0.80 (m, 6 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44
Hz, 3 H), 1.22 (t, J=7.29 Hz, 3 H), 1.83 (m, 1 H), 2.14 (m, 1 H), 2.72 (m, 2 H), 2.80 (m, 2 H), 2.98 (m, 2 H), 3.17 (m, 6 H), 3.67 (d, J=10.85 Hz, 1 H), 3.76 (m, 1 H), 3.87 (s, 3 H), 4.18 (m,
1 H), 4.42 (d, J=15.60 Hz, 1 H), 4.59 (d, J=15.60 Hz, 1 H), 6.39 (d, J=9.16 Hz, 1 H), 6.98 (d,
J=8.82 Hz, 2 H), 7.16 (m, 5 H), 7.42 (s, 1 H), 7.72 (d, J=8.82 Hz, 2 H)
Example 547 >
Η NMR (300 MHz, CDC13) δ ppm 0.87 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 0.95 (s, 9 H), 1.11 (m, 1 H), 1.83 (dd, J=14.75, 6.61 Hz, 1 H), 2.51 (q, J=8.82 Hz, 1 H), 2.70 (s, 3
H), 2.80 (m, 1 H), 3.01 (m, 2 H), 3.11 (m, 4 H), 3.29 (m, 1 H), 3.76 (m, 1 H), 3.87 (s, 3 H), 3.98 (s, 1 H), 4.18 (m, 1 H), 4.44 (d, J=7.46 Hz, 2 H), 6.11 (d, J=9.49 Hz, 1 H), 6.94 (s, 1 H), 6.98 (d, J=9.16 Hz, 2 H), 7.14 (m, 5 H), 7.73 (d, J=9.16 Hz, 2 H) Example 548
Η NMR (300 MHz, CDC13) δ ppm 0.73 (d, J=6.78 Hz, 3 H), 0.84 (dd, J=13.73, 6.95 Hz, 6 H), 0.92 (d, J=6.78 Hz, 3 H), 0.99 (m, 1 H), 1.36 (m, 1 H), 1.84 (m, 1 H), 1.94 (m, 1 H), 2.69 (s, 3 H), 2.76 (m, 3 H), 2.97 (m, 1 H), 3.13 (m, 6 H), 3.76 (m, 2 H), 3.87 (s, 3 H), 4.18 (m, 1 H), 4.36 (d, J=15.26 Hz, 1 H), 4.46 (d, J=15.26 Hz, 1 H), 6.40 (d, J=8.82 Hz, 1 H), 6.93 (s, 1 H), 6.98 (d, J=9.16 Hz, 2 H), 7.16 (m, 5 H), 7.73 (d, J=8.82 Hz, 2 H) Example 549 Η NMR (300 MHz, CDC13) δ ppm 0.90 (d, J=3.39 Hz, 3 H), 0.92 (d, J=3.39 Hz, 3 H), 1.89 (m, 1 H), 2.43 (m, 2 H), 2.69 (s, 3 H), 2.77 (m, 1 H), 2.91 (m, 2 H), 3.14 (m, 9 H), 3.87 (s, 3 H), 4.26 (m, 1 H), 4.41 (d, J=12.55 Hz, 1 H), 4.71 (m, 1 H), 5.23 (s, 1 H), 5.85 (s, 1 H), 6.79 (d, J=9.16 Hz, 1 H), 6.98 (s, 1 H), 6.99 (d, J=7.80 Hz, 2 H), 7.15 (m, 5 H), 7.75 (d, J=8.82 Hz, 2 H) Example 550
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.11 (m, 1 H), 2.71 (m, 2 H), 2.79 (m, 2 H), 2.96 (m, 1 H), 3.02 (m, 1 H), 3.16 (m, 7 H), 3.65 (d, J=10.85 Hz, 1 H), 3.76 (m, 1 H), 3.87 (s, 3 H), 4.17 (m, 1 H), 4.40 (d, J=15.26 Hz, 1 H), 4.50 (d, J=15.94 Hz, 1 H), 5.33 (s, 2 H), 6.41 (d, J=8.82 Hz, 1 H), 6.98 (d, J=8.82 Hz, 2 H), 7.14 (s, 1 H), 7.18 (m, 5 H), 7.72 (d, J=9.16 Hz^ 2 H) Example 551
Η NMR (300 MHz, CDC13) δ ppm 0.90 (d, J=6.44 Hz, 6 H), 1.67 (s, 2 H), 1.89 (m, 2 H), 2.09 (m, 2 H), 2.40 (m, 1 H), 2.70 (s, 3 H), 2.81 (dd, J=14.41, 11.02 Hz, 1 H), 2.90 (d, J=7.46 Hz, 2 H), 3.09 (m, 4 H), 3.15 (m, 3 H), 3.87 (s, 3 H), 4.30 (m, 2 H), 4.54 (d, J=15.26 Hz, 1 H), 5.52 (s, 1 H), 6.10 (s, 1 H), 6.74 (d, J=8.82 Hz, 1 H), 6.97 (m, 1 H), 7.00 (d, J=8.82 Hz, 2 H), 7.16 (m, 5 H), 7.74 (d, J=9.16 Hz, 2 H) Example 552 Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.13 (m, 1 H), 2.70 (m, 1 H),
2.78 (m, 1 H), 2.99 (m, 2 H), 3.14 (m, 5 H), 3.68 (d, J=10.85 Hz, 1 H), 3.76 (m, 1 H), 3.87 (s, 3 H), 4.20 (m, 1 H), 4.47 (d, J=4.07 Hz, 2 H), 6.36 (d, J=9.16 Hz, 1 H), 6.61 (s, 1 H), 6.98 (d, J=8.82 Hz, 2 H), 7.11 (m, 2 H), 7.21 (m, 6 H), 7.43 (d, J=8.14 Hz, 1 H), 7.53 (m, 1 H), 7.73 (d, J=9.16 Hz, 2 H) Example 553
Η NMR (300 MHz, CDC13) δ ppm 0.81 (dd, J=9.83, 6.78 Hz, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.14 (m, 1 H), 2.78 (m, 5 H), 3.06 (m, 7 H), 3.70 (d, J=11.19 Hz, 1 H), 3.82 (d, J=3.39 Hz, 1 H), 3.87 (s, 3 H), 4.21 (m, 1 H), 4.38 (d, J=15.26 Hz, 1 H), 4.67 (d, J=15.26 Hz, 1 H), 6.43 (d, J=8.82 Hz, 1 H), 6.98 (d, J=8.82 Hz, 2 H), 7.16 (m, 6 H), 7.56 (m, 1 H), 7.80 (d, J=8.14 Hz, 1 H), 8.03 (s, 1 H), 8.12 (d, J=8.48 Hz, 1 H), 8.83 (d, J=2.03 Hz, 1 H) Example 554
Η NMR (300 MHz, CDC13) δ ppm 0.80 (dd, J=6.61, 3.56 Hz, 3 H), 0.88 (m, 6 H), 0.92 (m, 3 H), 1.67 (s, 1 H), 1.85 (d, J=6.78 Hz, 1 H), 2.03 (m, 2 H), 2.16 (m, 1 H), 2.59 (m, 1 H), 2.79 (m, 2 H), 2.90 (m, 1 H), 3.10 (m, 4 H), 3.66 (m, 1 H), 3.80 (d, J=5.76 Hz, 1 H), 3.87 (s, 2 H), 4.07 (s, 1 H), 4.10 (m, 2 H), 4.20 (m, 1 H), 4.32 (m, 1 H), 4.94 (m, 1 H), 5.02 (m, 1 H), 5.37 (d, J=l 1.19 Hz, 1 H), 6.43 (d, J=8.82 Hz, 1 H), 6.98 (m, 2 H), 7.19 (m, 5 H), 7.73 (m, 2 H) Example 555
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.85 (m, 1 H), 2.14 (s, 3 H), 2.70 (m, 2 H), 2.79 (m, 2 H), 2.99 (m, 2 H), 3.17 (m, 5 H), 3.66 (d, J=10.85 Hz, 1 H), 3.77 (m, 1 H), 3.87 (s, 3 H), 3.95 (s, 2 H), 4.18 ( , 1 H), 4.42 (m, 2 H), 6.49 (d, J=9.16 Hz, 1 H), 6.97 (m, 2 H), 7.08 (m, 1 H), 7.14 (m, 5 H), 7.72 (d, J=9.16 Hz, 2 H) Example 556
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.85 (m, 1 H), 2.14 (m, 1 H), 2.72 (m, 1 H), 2.80 (m, 2 H), 2.95 (m, 1 H), 3.07 (m, 2 H), 3.16 (m, 2 H), 3.24 (m, 2 H), 3.66 (d, J=10.85 Hz, 1 H), 3.79 (m, 1 H), 3.87 (s, 3 H), 4.08 (s, 2 H), 4.18 (m, 1 H), 4.44 (m, 2 H), 6.51 (d, J=9.16 Hz, 1 H), 6.98 (d, J=9.16 Hz, 2 H), 7.14 (s, 1 H), 7.18 (m, 5 H), 7.72 (d, J=8.82 Hz, 2 H) Example 557 Η NMR (300 MHz, CDC13) δ ppm 0.73 (d, J=6.44 Hz, 3 H), 0.85 (m, 9 H), 1.88 (m, 1 H), 2.23 (s, 3 H), 2.88 (m, 5 H), 3.12 (m, 7 H), 3.60 (d, J=10.51 Hz, 1 H), 3.87 (s, 3 H), 3.95 (m, 1 H), 4.17 (m, 1 H), 4.35 (m, 2 H), 6.71 (s, 1 H), 6.97 (m, 2 H), 7.18 (m, 5 H), 7.73 (m, 2 H) Example 558 Η NMR (300 MHz, CDC13) δ ppm 0.81 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.78 Hz, 6 H), 0.92 (d, J=6.44 Hz, 3 H), 1.85 (m, 1 H), 2.18 (m, 1 H), 2.78 (m, 3 H), 3.00 (m, 2 H), 3.18 (m, 4 H), 3.71 (d, J=10.85 Hz, 1 H), 3.78 (s, 1 H), 3.87 (d, J=3.05 Hz, 3 H), 4.21 (m, 1 H), 4.51 (d, J=15.94 Hz, 1 H), 4.80 (d, J=15.60 Hz, 1 H), 6.43 (d, J=8.82 Hz, 1 H), 6.98 (m, 2 H), 7.18 (m, 7 H), 7.33 (d, J=7.46 Hz, 1 H), 7.44 (m, 2 H), 7.73 (m, 2 H), 8.17 (d, J=8.48 Hz, 1 H) Example 559 Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.84 (t, J=6.95 Hz, 6 H), 0.91 (d, J=6.44 Hz, 3 H), 0.97 (m, 1 H), 1.29 (m, 1 H), 1.82 (dd, J=14.75, 6.95 Hz, 1 H), 1.97 (m, 1 H), 2.79 (m, 2 H), 2.99 (m, 3 H), 3.10 (m, 2 H), 3.24 (t, J=7.80 Hz, 2 H), 3.76 (d, J=10.85 Hz, 2 H), 3.85 (s, 3 H), 3.87 (s, 3 H), 4.22 (m, 1 H), 4.61 (d, J=15.26 Hz, 1 H), 4.81 (m, 1 H), 6.35 (d, J=8.82 Hz, 1 H), 6.98 (m, 2 H), 7.15 (m, 6 H), 7.35 (m, 3 H), 7.71 (m, 2 H), 7.79 (m, I H)
Example 560 Η NMR (300 MHz, CDC13) δ ppm 0.81 (d, J=6.44 Hz, 3 H), 0.86 (t, J=6.78 Hz, 6 H), 0.92 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.16 (m, 1 H), 2.75 (m, 3 H), 3.01 (m, 3 H), 3.14 (m, 3 H), 3.72 (d, J=11.19 Hz, 1 H), 3.79 (m, 1 H), 3.87 (m, 3 H), 3.98 (s, 3 H), 4.19 (m, 1 H), 4.45 (s, 1 H), 4.79 (d, J=15.26 Hz, 1 H), 6.41 (d, J=9.16 Hz, 1 H), 6.76 (s, 1 H), 6.98 (d, J=9.16 Hz, 2 H), 7.18 (m, 6 H), 7.50 (t, J=7.46 Hz, 1 H), 7.68 (s, 1 H), 7.72 (m, 2 H), 8.00 (s, 1 H), 8.16 (d, J=8.14 Hz, I H) Example 561
Η NMR (300 MHz, CDC13) δ ppm 0.79 (t, J=6.10 Hz, 3 H), 0.86 (m, 6 H), 0.92 (d, J=6.78 Hz, 3 H), 1.85 (m, 3 H), 2.16 (m, 1 H), 2.78 (m, 2 H), 3.00 (m, 2 H), 3.21 (m, 4 H), 3.70 (d, J=10.85 Hz, 1 H), 3.78 (m, 1 H), 3.87 (s, 3 H), 4.22 (d, J=9.49 Hz, 1 H), 4.54 (d, J=15.94 Hz, 1 H), 4.84 (d, J=15.94 Hz, 1 H), 6.40 (d, J=8.82 Hz, 1 H), 6.98 (d, J=8.82 Hz, 2 H), 7.17 (m, 6 H), 7.72 (m, 2 H), 7.78 (m, 2 H), 8.05 (m, 1 H), 8.12 (m, 1 H) Example 562
Η NMR (300 MHz, CDC13) δ ppm 0.91 (d, J=3.73 Hz, 3 H), 0.93 (d, J=4.07 Hz, 3 H), 1.87 (m, 1 H), 2.37 (dd, J=14.58, 6.44 Hz, 1 H), 2.49 (m, 1 H), 2.63 (d, J=4.75 Hz, 3 H), 2.70 (m, 3 H), 2.75 (m, 1 H), 2.92 (m, 2 H), 3.13 (m, 5 H), 3.79 (s, 1 H), 3.87 (s, 3 H), 4.23 (m, 1 H), 4.41 (m, 2 H), 4.64 (dd, J=8.14, 6.44 Hz, 1 H), 5.79 (s, 1 H), 6.78 (d, J=9.16 Hz, 1 H), 6.99 (m, 3 H), 7.16 (m, 6 H), 7.75 (m, 2 H) Example 563 Η NMR (300 MHz, CDC13) δ ppm 0.91 (d, J=5.09 Hz, 3 H), 0.93 (d, J=4.75 Hz, 3 H), 0.99 (t, J=7.29 Hz, 3 H), 1.88 (dd, J=13.73, 6.95 Hz, 1 H), 2.35 (dd, J=14.58, 6.44 Hz, 1 H), 2.48 (q, J=8.48 Hz, 1 H), 2.69 (s, 3 H), 2.76 (m, 1 H), 2.92 (m, 2 H), 3.14 (m, 6 H), 3.81 (m, 1 H), 3.87 (s, 3 H), 3.91 (d, J=3.39 Hz, 1 H), 4.22 (dd, J=9.66, 5.26 Hz, 1 H), 4.41 (m, 2 H), 4.64 (dd, J=8.31, 6.61 Hz, 1 H), 5.76 (s, 1 H), 6.75 (d, J=8.82 Hz, 1 H), 6.99 (m, 3 H), 7.16 (m, 6 H), 7.75 (m, 2 H) Example 564
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.83 (d, J=7.12 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.01 (m, 1 H), 1.32 (m, 1 H), 1.84 (m, 3 H), 1.97 (m, 1 H), 2.78 (m, 3 H), 3.06 (m, 4 H), 3.81 (m, 2 H), 3.87 (s, 3 H), 3.91 (d, J=2.71 Hz, 1 H), 4.23 (m, 1 H), 4.79 (m, 2 H), 6.47 (d, J=8.82 Hz, 1 H), 6.97 (m, 2 H), 7.15 (m, 6 H), 7.27 (s, 1 H), 7.59 (m, 1 H), 7.75 (m, 2 H), 8.15 (d, J=8.48 Hz, 2 H), 8.88 (d, J=4.41 Hz, 1 H) Example 565 Η NMR (300 MHz, CD3OD) δ ppm 0.73 (d, J=6.44 Hz, 3 H), 0.86 (m, 6 H), 0.91 (m, 3 H), 0.99 (m, 1 H), 1.31 (m, 1 H), 1.85 (m, 1 H), 2.00 (m, 1 H), 2.48 (m, 2 H), 2.90 (m, 1 H), 3.05 (m, 4 H), 3.18 (m, 1 H), 3.41 (m, 1 H), 3.76 (m, 1 H), 3.83 (s, 1 H), 3.87 (s, 3 H), 4.13 (m, 1 H), 4.49 (m, 2 H), 6.99 (m, 5 H), 7.08 (m, 2 H), 7.14 (m, 2 H), 7.25 (m, 1 H), 7.59 (s, 2 H), 7.78 (m, 2 H), 8.16 (s, I H) Example 566
Η NMR (300 MHz, CDC13) δ ppm 0.76 (t, J=6.61 Hz, 3 H), 0.80 (d, J=6.78 Hz, 3 H), 1.16 (d, J=6.44 Hz, 1 H), 1.29 (d, J=11.19 Hz, 1 H), 1.59 (m, 8 H), 2.13 (m, 2 H), 2.71 (m, 1 H), 2.90 (m, 1 H), 3.11 (m, 4 H), 3.48 (d, J=5.76 Hz, 3 H), 3.67 (d, J=10.85 Hz, 1 H), 3.80 (m, 1 H), 3.86 (d, J=3.73 Hz, 3 H), 3.88 (s, 1 H), 4.23 (m, 1 H), 4.45 (q, J=15.60 Hz, 2 H), 4.70 (d, J=4.07 Hz, 2 H), 6.53 (d, J=8.82 Hz, 1 H), 6.98 (m, 2 H), 7.11 (d, J=2.37 Hz, 1 H), 7.20 (m, 6 H), 7.72 (d, J=9.16 Hz, 2 H) Example 567 Η NMR (300 MHz, CD3OD) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.88 (m, 6 H), 0.90 (m, 3 H), 1.02 (m, 1 H), 1.41 (m, 1 H), 1.88 (m, 1 H), 1.98 (m, 1 H), 2.51 (dd, J=13.73, 11.36 Hz, 1 H), 2.62 (m, 1 H), 2.90 (dd, J=13.73, 6.95 Hz, 1 H), 3.00 (dd, J=14.41, 8.65 Hz, 2 H), 3.13 (m, 3 H), 3.24 (m, 2 H), 3.41 (dd, J=14.58, 3.73 Hz, 1 H), 3.77 (m, 1 H), 3.87 (d, J=11.19 Hz, 1 H), 3.87 (s, 3 H), 4.16 (m, 1 H), 4.52 (d, J=15.94 Hz, 1 H), 4.78 (m, 1 H), 7.08 (m, 4 H), 7.16 (m, 3 H), 7.46 (d, J=8.48 Hz, 1 H), 7.59 (m, 1 H), 7.76 (m, 3 H), 7.92 (d, J=8.14 Hz, 1 H), 8.02 (d, J=8.48 Hz, 1 H), 8.33 (d, J=8.48 Hz, 1 H) Example 568
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.78 Hz, 3 H), 0.82 (t, J=7.29 Hz, 3 H), 0.96 (m, 1 H), 1.18 (m, 1 H), 1.29 (m, 2 H), 1.59 (m, 8 H), 1.95 (m, 1 H), 2.10 (dd, J=15.26, 7.80 Hz, 1 H), 2.77 (m, 2 H), 2.91 (dd, J=13.22, 7.12 Hz, 1 H), 3.06 (m, 3 H), 3.17 (m, 2 H), 3.77 (m, 1 H), 3.80 (s, 3 H), 3.87 (s, 3 H), 4.24 (m, 1 H), 4.50 (d, J=15.26 Hz, 1 H), 4.76 (d,
J=15.26 Hz, 1 H), 6.38 (d, J=9.16 Hz, 1 H), 6.98 (m, 2 H), 7.15 (m, 6 H), 7.31 (m, 3 H), 7.72
(m, 2 H), 7.75 (m, 1 H)
Example 569
Η NMR (300 MHz, DMSO-d6) δ ppm 0.62 (d, J=6.44 Hz, 3 H), 0.78 (m, 6 H), 0.82 (d, J=3.05 Hz, 3 H), 0.89 (m, 1 H), 1.73 (s, 1 H), 1.97 (m, 1 H), 2.41 (dd, J=13.73, 11.02 Hz, 1 H), 2.61 (t, J=7.12 Hz, 1 H), 2.80 (dd, J=13.90, 6.78 Hz, 1 H), 2.97 (m, 3 H), 3.10 (m, 1 H), 3.21 (dd, J=14.58, 2.37 Hz, 1 H), 3.38 (s, 3 H), 3.44 (m, 1 H), 3.51 (s, 1 H), 3.60 (m, 1 H), 3.83 (s, 3 H), 3.89 (m, 2 H), 4.37 (s, 2 H), 4.68 (s, 2 H), 4.93 (d, J=6.44 Hz, 1 H), 7.07 (m, 7 H), 7.41 (s, 1 H), 7.72 (d, J=8.82 Hz, 2 H), 7.87 (d, J=9.16 Hz, 1 H) Example 570
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.86 (dd, J=8.82, 6.78 Hz, 6 H), 0.92 (d, J=6.78 Hz, 3 H), 1.02 (m, 1 H), 1.35 (m, 1 H), 1.84 (m, 1 H), 1.97 (d, J=10.85 Hz, 1 H), 2.79 (m, 1 H), 2.88 (s, 3 H), 2.96 (s, 3 H), 3.08 (m, 2 H), 3.79 (m, 2 H), 3.87 (s, 3 H), 4.20 (m, 2 H), 4.49 (d, J=15.60 Hz, 1 H), 6.41 (d, J=8.82 Hz, 1 H), 6.98 (m, 2 H), 7.18 (m, 5 H), 7.47 (m, 3 H), 7.58 (m, 1 H), 7.73 (m, 2 H), 8.02 (s, 1 H) Example 571 Η NMR (300 MHz, CDC13) δ ppm 0.87 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 0.96 (s, 9 H), 1.84 (m, 1 H), 2.56 (q, J=8.93 Hz, 1 H), 2.71 (dd, J=14.41, 10.68 Hz, 1 H), 2.82 (m, 1 H), 2.97 (m, 2 H), 3.10 (m, 4 H), 3.29 (m, 1 H), 3.56 (dd, J=7.80, 5.43 Hz, 1 H), 3.82 (m, 3 H), 3.87 (d, J=4.07 Hz, 3 H), 3.97 (d, J=11.53 Hz, 1 H), 4.24 (m, 1 H), 4.57 (d, J=15.26 Hz, 1 H), 4.75 (m, 1 H), 6.13 (d, J=9.16 Hz, 1 H), 6.99 (m, 2 H), 7.12 (m, 5 H), 7.32 (m, 3 H), 7.72 (m, 2 H), 7.76 (m, 1 H) Example 572
Η NMR (300 MHz, CDC13) δ ppm 0.89 (d, J=6.78 Hz, 3 H), 1.90 (d, J=6.44 Hz, 1 H), 2.31 (s, 1 H), 2.68 (m, 3 H), 2.79 (s, 2 H), 2.89 (t, J=7.80 Hz, 2 H), 3.08 (m, 4 H), 3.25 (m, 1 H), 3.49 (s, 1 H), 3.75 (s, 1 H), 3.87 (s, 3 H), 3.91 (d, J=7.46 Hz, 1 H), 3.97 (t, J=4.75 Hz, 2 H), 4.46 (d, J=13.90 Hz, 5 H), 6.97 (m, 4 H), 7.20 (m, 5 H), 7.75 (m, 2 H), 7.98 (m, 1 H) Example 573
Η NMR (300 MHz, CDC13) δ ppm 0.86 (m, 6 H), 1.87 (m, 2 H), 2.65 (s, 1 H), 2.69 (s, 3 H), 2.88 (m, 2 H), 3.05 (m, 1 H), 3.27 (m, 2 H), 3.57 (dd, J=14.07, 7.63 Hz, 2 H), 3.57 (dd, J=14.07, 7.63 Hz, 1 H), 3.86 (d, J=3.39 Hz, 3 H), 3.92 (m, 1 H), 4.23 (dd, J=14.41, 4.92 Hz, 1 H), 4.33 (m, 2 H), 4.43 (m, 2 H), 4.51 (d, J=2.37 Hz, 1 H), 4.73 (d, J=11.19 Hz, 2 H), 5.43 (s, 1 H), 6.98 (m, 5 H), 7.16 (m, 3 H), 7.22 (d, J=6.10 Hz, 1 H), 7.59 (m, 1 H), 7.73 (m, 2 H) Example 574
Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.44 Hz, 3 H), 0.85 (m, 6 H), 0.92 (d, J=6.44 Hz, 3 H), 0.99 (m, 1 H), 1.39 (d, J=25.77 Hz, 1 H), 1.86 (m, 1 H), 1.96 (s, 1 H), 2.73 (m, 1 H), 2.79 (m, 2 H), 2.96 (m, 1 H), 3.01 (m, 1 H), 3.14 (m, 5 H), 3.48 (s, 3 H), 3.76 (m, 2 H), 3.88 (m, 3 H), 4.19 (d, J=9.49 Hz, 1 H), 4.35 (d, J=15.60 Hz, 1 H), 4.55 (s, 2 H), 4.58 (m, 1 H), 6.40 (d, J=8.82 Hz, 1 H), 6.98 (m, 2 H), 7.12 (d, J=8.14 Hz, 1 H), 7.19 (m, 5 H), 7.31 (d, J=7.46 Hz, 1 H), 7.67 (t, J=7.63 Hz, 1 H), 7.72 (m, 2 H) Example 575 Η NMR (300 MHz, CDC13) δ ppm 0.79 (m, 9 H), 0.86 (t, J=7.29 Hz, 3 H), 1.02 (m, 1 H), 1.43 (m, 2 H), 1.83 (m, 1 H), 2.02 (d, J=13.56 Hz, 1 H), 2.34 (d, J=5.09 Hz, 3 H), 2.85 (m, 3 H), 3.08 (m, 5 H), 3.78 (d, J=10.85 Hz, 1 H), 3.87 (s, 3 H), 3.95 (m, 1 H), 4.20 (m, 2 H), 4.51 (d, J=16.28 Hz, 1 H), 4.64 (d, J=3.39 Hz, 1 H), 6.57 (d, J=7.80 Hz, 1 H), 6.98 (m, 2 H), 7.10 (dd, J=5.09, 1.70 Hz, 1 H), 7.18 (m, 5 H), 7.72 (m, 3 H), 8.55 (d, J=5.09 Hz, 1 H) Example 576
Η NMR (300 MHz, DMSO-d6) δ ppm 0.63 (d, J=6.44 Hz, 3 H), 0.81 (m, 9 H), 0.93 (m, 1 H), 1.29 (m, 1 H), 1.75 (s, 1 H), 1.95 (m, 1 H), 2.41 (dd, J=13.56, 10.85 Hz, 1 H), 2.59 (m, 1 H), 2.80 (dd, J=13.56, 6.78 Hz, 1 H), 2.92 (dd, J=13.90, 8.48 Hz, 2 H), 3.07 (m, 1 H), 3.21 (m, 1 H), 3.59 (m, 1 H), 3.84 (s, 3 H), 3.88 (m, 2 H), 4.47 (d, J=3.05 Hz, 2 H), 4.93 (d, J=6.44 Hz, 1 H), 6.98 (m, 1 H), 7.07 (dd, J=14.92, 8.14 Hz, 7 H), 7.48 (m, 1 H), 7.57 (s, 1 H), 7.72 (m, 2 H), 7.91 (m, 1 H), 7.96 (m, 1 H), 8.11 (d, J=7.80 Hz, 1 H), 8.63 (d, J=4.07 Hz, 1 H) Example 577
Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.25 Hz, 3 H), 0.86 (m, 6 H), 0.92 (d, J=6.62 Hz, 3 H), 1.00 (m, 1 H), 1.37 (m, 1 H), 1.84 (m, 1 H), 1.96 (m, 1 H), 2.76 (m, 2 H), 2.97 (m, 1 H), 3.02 (dd, J=11.95, 3.13 Hz, 1 H), 3.10 (m, 2 H), 3.27 (m, 2 H), 3.76 (m, 2 H), 3.87 (m, 4 H), 4.13 (m, 1 H), 4.20 (m, 1 H), 4.52 (m, 2 H), 6.40 (d, J=9.19 Hz, 1 H), 6.97 (m, 2 H), 7.16 (m, 6 H), 7.37 (dd, J=8.46, 4.41 Hz, 1 H), 7.73 (m, 2 H), 8.21 (m, 1 H), 8.65 (dd, J=4.78, 1.84 Hz, 1 H), 9.15 (d, J=2.21 Hz, 1 H) Example 578
Η NMR (300 MHz, CDC13) δ ppm 0.88 (d, J=6.62 Hz, 3 H), 0.93 (d, J=6.62 Hz, 3 H), 0.95 (s, 9 H), 1.84 (dd, J=7.91, 6.43 Hz, 1 H), 2.52 (q, J=8.82 Hz, 1 H), 2.69 (dd, J=14.16, 10.48 Hz, 1 H), 2.79 (m, 1 H), 2.97 (m, 1 H), 3.06 (m, 1 H), 3.17 (m, 2 H), 3.18 (m, 1 H), 3.30 (m, 1 H), 3.49 (s, 3 H), 3.75 (m, 1 H), 3.85 (d, J=2.57 Hz, 1 H), 3.87 (s, 3 H), 3.98 (s, 1 H), 4.20 (m, 1 H), 4.47 (m, 2 H), 4.71 (s, 2 H), 6.14 (d, J=8.82 Hz, 1 H), 6.98 (m, 2 H), 7.11 (s, 1 H), 7.15 (m, 5 H), 7.73 (m, 2 H) Example 579 Η NMR (300 MHz, DMSO-d6) δ ppm 0.83 (m, 15 H), 1.96 (m, 1 H), 2.22 (m, 1 H), 2.36 (dd, J=13.24, 11.40 Hz, 1 H), 2.81 (m, 2 H), 2.93 (dd, J=15.26, 5.70 Hz, 1 H), 3.02 (m, 3 H), 3.15 (m, 3 H), 3.83 (s, 3 H), 3.99 (s, 1 H), 4.49 (m, 2 H), 6.94 (m, 1 H), 7.07 (m, 7 H), 7.56 (dd, J=7.54, 5.33 Hz, 1 H), 7.61 (s, 1 H), 7.72 (m, 2 H), 7.98 (d, J=9.56 Hz, 1 H), 8.33 (m, 1 H), 8.67 (dd, J=4.78, 1.47 Hz, 1 H), 9.15 (d, J=1.47 Hz, 1 H) Example 580
Η NMR (500 MHz, DMSO-d6) δ ppm 0.62 (m, 3 H), 0.78 (m, 6 H), 0.82 (m, 3 H), 0.92 (m, 1 H), 1.27 (m, 1 H), 1.75 (m, 1 H), 1.95 (m, 1 H), 2.42 (dd, J=13.43, 10.99 Hz, 1 H), 2.60 (m, 1 H), 2.71 (s, 3 H), 2.81 (m, 1 H), 2.92 (dd, J=14.04, 8.54 Hz, 1 H), 2.97 (dd, J=9.46, 5.80 Hz, 1 H), 3.02 (m, 1 H), 3.09 (m, 1 H), 3.20 (m, 1 H), 3.35 (d, J=8.54 Hz, 1 H), 3.58 (m, 1 H), 3.84 (s, 3 H), 3.86 (m, 1 H), 3.92 (m, 1 H), 4.43 (m, 2 H), 4.92 (d, J=6.71 Hz, 1 H), 6.99 (t, J=7.32 Hz, 1 H), 7.08 (m, 8 H), 7.43 (s, 1 H), 7.72 (d, J=8.54 Hz, 2 H), 7.86 (d, J=9.77 Hz, I H)
Example 581 Η NMR (300 MHz, DMSO-d6) δ ppm 0.62 (t, J=6.62 Hz, 3 H), 0.80 (m, 9 H), 0.91 (m, 1 H), 1.24 (t, J=7.54 Hz, 3 H), 1.73 (d, J=8.09 Hz, 1 H), 1.95 (m, 1 H), 2.41 (dd, J=13.42, 11.21 Hz, 1 H), 2.60 (m, 1 H), 2.80 (m, 2 H), 2.92 (dd, J=13.79, 8.64 Hz, 2 H), 3.04 (m, 4 H), 3.08 (m, 1 H), 3.21 (m, 3 H), 3.58 (m, 1 H), 3.84 (s, 3 H), 3.87 (m, 1 H), 4.51 (m, 2 H), 4.93 (m, 1 H), 6.97 (m, 1 H), 7.07 (m, 5 H), 7.66 (s, 1 H), 7.70 (m, 2 H), 7.73 (m, 2 H), 7.90 (d, J=9.56 Hz, 1 H), 8.59 (d, J=5.15 Hz, 1 H) Example 582
Η NMR (300 MHz, CD3OD) δ ppm 0.73 (d, J=6.62 Hz, 3 H), 0.85 (dd, J=16.55, 6.99 Hz, 6 H), 0.91 (d, J=6.62 Hz, 3 H), 1.00 (m, 1 H), 1.33 (m, 1 H), 1.83 (dd, J=l 1.40, 3.68 Hz, 1 H), 2.00 (m, 1 H), 2.51 (m, 1 H), 2.58 (s, 3 H), 2.91 (m, 2 H), 3.06 (m, 6 H), 3.23 (m, 3 H), 3.40 (dd, J=14.71, 3.68 Hz, 1 H), 3.75 (m, 1 H), 3.82 (s, 1 H), 3.87 (s, 3 H), 4.11 (m, 1 H), 4.54 (m, 2 H), 7.01 (m, 1 H), 7.09 (m, 5 H), 7.40 (d, J=8.82 Hz, 1 H), 7.46 (s, 1 H), 7.77 (d, J=8.82 Hz, 2 H), 8.23 (d, J=2.21 Hz, 1 H), 8.26 (d, J=2.57 Hz, 1 H), 9.00 (d, J=2.21 Hz, 1 H) Example 583
Η NMR (300 MHz, CDC13) δ ppm 0.88 (d, J=6.62 Hz, 3 H), 0.92 (d, J=6.62 Hz, 3 H), 0.96 (s, 9 H), 1.84 (m, 1 H), 2.60 (q, J=8.70 Hz, 1 H), 2.72 (dd, J=14.16, 10.48 Hz, 2 H), 2.80 (m, 2 H), 2.97 (m, 2 H), 3.04 (d, J=3.68 Hz, 1 H), 3.13 (m, 6 H), 3.32 (m, 1 H), 3.80 (m, 1 H), 3.85 (t, J=2.94 Hz, 1 H), 4.00 (s, 1 H), 4.26 (m, 1 H), 4.67 (dd, J=65.63, 15.26 Hz, 2 H), 6.11 (d, J=9.19 Hz, 1 H), 6.99 (m, 2 H), 7.11 (m, 5 H), 7.23 (m, 1 H), 7.73 (m, 2 H), 8.01 (dd, J=8.09, 1.47 Hz, 1 H), 8.39 (dd, J=4.78, 1.47 Hz, 1 H) Example 584 *
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.62 Hz, 3 H), 0.84 (m, 6 H), 0.92 (d, J=6.25 Hz, 3 H), 1.33 (m, 2 H), 1.83 (m, 2 H), 1.97 (m, 2 H), 2.78 (m, 3 H), 3.01 (m, 2 H), 3.14 (m, 2 H), 3.80 (m, 3 H), 3.87 (s, 3 H), 4.10 (m, 1 H), 4.23 (m, 1 H), 4.49 (d, J=15.08 Hz, 1 H),
4.79 (d, J=15.44 Hz, 1 H), 6.33 (d, J=8.82 Hz, 2 H), 6.98 (m, 2 H), 7.16 (m, 7 H), 7.73 (m, 2 H), 8.00 (dd, J=8.09, 1.47 Hz, 1 H), 8.39 (dd, J=4.78, 1.47 Hz, 1 H)
Example 585
Η NMR (300 MHz, CD3OD) δ ppm 0.74 (d, J=6.62 Hz, 3 H), 0.84 (m, 3 H), 0.97 (m, 1 H), 1.19 (m, 2 H), 1.34 (m, 2 H), 1.55 (m, 5 H), 1.69 (m, 3 H), 1.86 (m, 1 H), 2.26 (m, 1 H), 2.52 (m, 3 H), 3.01 (m, 1 H), 3.17 (m, 1 H), 3.42 (dd, J=14.71, 4.04 Hz, 1 H), 3.79 (m, 2 H), 3.87 (s, 3 H), 4.13 (m, 1 H), 4.56 (d, J=5.52 Hz, 2 H), 7.05 (m, 6 H), 7.17 (m, 3 H), 7.51 (s, 1 H), 7.54 (m, 1 H), 7.77 (m, 2 H), 8.37 (m, 1 H), 8.60 (dd, J=4.96, 1.65 Hz, 1 H), 9.14 (d, J=1.47 Hz, I H) Example 586
Η NMR (300 MHz, DMSO-d6) δ ppm 0.58 (d, J=6,62 Hz, 3 H), 0.77 (m, 3 H), 0.87 (q, J=7.23 Hz, 2 H), 0.95 (m, 9 H), 1.23 (m, 2 H), 1.76 (m, 1 H), 2.43 (m, 1 H), 2.59 (m, 1 H),
2.80 (d, J=14.71 Hz, 1 H), 2.97 (m, 3 H), 3.09 (m, 1 H), 3.21 (d, J=9.56 Hz, 1 H), 3.31 (m, 1 H), 3.74 (s, 2 H), 3.83 (d, J=5.88 Hz, 2 H), 4.45 (d, J=15.07 Hz, 2 H), 6.97 (m, 1 H), 7.07 (m, 7 H), 7.56 (m, 1 H), 7.60 (s, 1 H), 7.75 (m, 2 H), 7.87 (d, J=9.19 Hz, 1 H), 8.33 (m, 1 H), 8.68 (dd, J=4.78, 1.47 Hz, 1 H), 9.15 (d, J=1.47 Hz, 1 H) Example 587 Η NMR (300 MHz, CDC13) δ ppn 0.77 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.14 (m, 1 H), 2.75 (m, 3 H), 2.99 (m, 3 H), 3.19 (m, 4 H), 3.66 (d, J=10.85 Hz, 1 H), 3.76 (m, 1 H), 3.87 (s, 3 H), 4.19 (m, 3 H), 4.38 (d, J=15.26 Hz, 1 H), 4.47 (d, J=15.60 Hz, 1 H), 6.48 (d, J=8.82 Hz, 1 H), 6.98 (m, 4 H), 7.16 (m, 6 H), 7.72 (d, J=8.82 Hz, 2 H) Example 588
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.83 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.84 (m, 2 H), 2.02 (s, 3 H), 2.15 (m, 1 H), 2.76 (m, 4 H), 2.95 (m, 1 H), 3.05 (dd, J=14.92, 3.73 Hz, 1 H), 3.18 (m, 3 H), 3.65 (d, J=10.85 Hz, 1 H), 3.78 (m, 1 H), 3.87 (s, 3 H), 4.15 (m, 1 H), 4.38 (d, J=15.60 Hz, 1 H), 4.48 (d, J=15.26 Hz, 1 H), 4.70 (d, J=5.43 Hz, 2 H), 6.32 (s, 1 H), 6.56 (d, J=9.16 Hz, 1 H), 6.98 (d, J=8.82 Hz, 2 H), 7.05 (s, 1 H), 7.16 (m, 5 H), 7.71 (d, J=9.16 Hz, 2 H) Example 589 Η NMR (300 MHz, CDC13) δ ppm 0.75 (s, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.15 (m, 1 H), 2.71 (m, 1 H), 2.75 (m, 2 H), 2.81 (m, 1 H), 2.95 (m, 1 H), 3.04 (dd, J=14.41, 11.36 Hz, 1 H), 3.11 (m, 4 H), 3.21 (m, 1 H), 3.64 (d, J=10.85 Hz, 1 H), 3.78 (m, 1 H), 3.87 (s, 3 H), 4.17 (m, 1 H), 4.44 (q, J=15.37 Hz, 2 H), 4.92 (s, 2 H), 6.55 (d, J=9.16 Hz, 1 H), 6.98 (d, J=9.16 Hz, 2 H), 7.09 (s, 1 H), 7.17 (m, 5 H), 7.72 (d, J=9.16 Hz, 2 H) Example 590
ΗNMR (300 MHz, CDC13) δ ppm 0.80 (t, J=6.61 Hz, 6 H), 0.86 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.83 (m, 1 H), 2.16 (m, 1 H), 2.70 (s, 1 H), 2.75 (d, J=2.03 Hz, 6 H),
2.80 (m, 1 H), 2.94 (m, 1 H), 3.00 (dd, J=12.04, 3.22 Hz, 1 H), 3.10 (dd, J=9.32, 4.92 Hz, 2 H), 3.16 (m, 3 H), 3.24 (m, 1 H), 3.65 (d, J=10.85 Hz, 1 H), 3.78 (m, 1 H), 3.87 (s, 3 H), 4.19 (m, 1 H), 4.28 (s, 2 H), 4.49 (m, 2 H), 6.45 (d, J=8.82 Hz, 1 H), 6.97 (m, 2 H), 7.17 (m, 5 H),
7.25 (s, 1 H), 7.72 (m, 2 H)
Example 591
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.86
(d, J=6.44 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 1.85 (m, 1 H), 2.16 (m, 1 H), 2.72 (m, 1 H), 2.79 (dd, J=13.73, 6.27 Hz, 2 H), 2.92 (m, 1 H), 2.98 (s, 3 H), 3.06 (dd, J=14.24, 3.73 Hz, 2
H), 3.18 (m, 4 H), 3.64 (d, J=10.85 Hz, 1 H), 3.79 (m, 1 H), 3.87 (s, 3 H), 4.18 (m, 1 H), 4.41
(m, 2 H), 4.60 (d, J=6.10 Hz, 2 H), 5.51 (t, J=6.27 Hz, 1 H), 6.61 (d, J=9.16 Hz, 1 H), 6.98
(m, 2 H), 7.08 (s, 1 H), 7.18 (m, 5 H), 7.72 (m, 2 H)
Example 592 Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.44 Hz, 3 H), 0.79 (d, J=6.44 Hz, 3 H), 0.84
(d, J=6.44 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 1.86 (m, 1 H), 2.14 (m, 1 H), 2.71 (m, 2 H),
2.81 (m, 2 H), 2.99 (m, 2 H), 3.19 (m, 4 H), 3.69 (d, J=10.85 Hz, 1 H), 3.82 (s, 1 H), 3.87 (s, 3 H), 4.22 (s, 1 H), 4.54 (m, 2 H), 6.88 (m, 1 H), 6.98 (d, J=8.82 Hz, 2 H), 7.13 (d, J=6.10 Hz, 5 H), 7.45 (s, 1 H), 7.72 (d, J=9.16 Hz, 2 H), 8.02 (s, 1 H) Example 593 Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.86 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.15 (m, 1 H), 2.69 (m, 1 H), 2.78 (m, 2 H), 2.94 (d, J=8.14 Hz, 1 H), 2.98 (dd, J=5.76, 2.71 Hz, 1 H), 3.04 (d, J=3.05 Hz, 1 H), 3.13 (m, 3 H), 3.21 (m, 1 H), 3.66 (d, J=10.85 Hz, 1 H), 3.71 (s, 3 H), 3.78 (m, 1 H), 3.87 (s, 3 H), 4.17 (m, 1 H), 4.42 (m, 2 H), 4.63 (d, J=6.10 Hz, 2 H), 5.53 (s, 1 H), 6.60 (d, J=9.16 Hz, 1 H), 6.97 (m, 2 H), 7.06 (s, 1 H), 7.16 (m, 5 H), 7.72 (m, 2 H) Example 594
, Η NMR (300 MHz, CDC13) δ ppm 0.79 (dd, J=9.16, 6.44 Hz, 6 H), 0.86 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.83 (dd, J=14.41, 6.61 Hz, 1 H), 2.14 (m, 1 H), 2.72 (m, 1 H), 2.80 (m, 2 H), 2.97 (s, 3 H), 3.16 (m, 7 H), 3.66 (d, J=10.85 Hz, 1 H), 3.79 (m, 1 H), 3.87 (s, 3 H), 4.20 (m, 1 H), 4.47 (m, 2 H), 4.59 (s, 2 H), 6.55 (d, J=9.16 Hz, 1 H), 6.98 (d, J=9.16 Hz, 2 H), 7.18 (m, 6 H), 7.71 (m, 2 H) Example 595 Η NMR (300 MHz, CDC13) δ ppm 0.80 (m, 6 H), 0.86 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 1.39 (t, J=7.29 Hz, 6 H), 1.83 (m, 1 H), 2.15 (m, 1 H), 2.73 (m, 2 H), 2.82 (m, 2 H), 2.95 (m, 1 H), 3.05 (dd, J=16.28, 3.73 Hz, 2 H), 3.17 (m, 7 H), 3.66 (d, J=10.85 Hz, 1 H), 3.78 (m, 1 H), 3.87 (s, 3 H), 4.18 (m, 1 H), 4.37 (d, J=15.94 Hz, 1 H), 4.57 (s, 2 H), 4.57 (m, 1 H), 6.52 (d, J=9.16 Hz, 1 H), 6.98 (m, 2 H), 7.17 (m, 5 H), 7.24 (s, 1 H), 7.72 (m, 2 H) Example 596 Η NMR (300 MHz, CD3OD) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.90 (d, J=6.78 Hz, 3 H), 1.15 (d, J=6.78 Hz, 6 H), 1.27 (d, J=8.48 Hz, 1 H), 2.02 (m, 2 H), 2.51 (dd, J=13.90, 11.19 Hz, 1 H), 2.59 (m, 1 H), 2.90 (m, 1 H), 3.02 (m, 2 H), 3.10 (m, 2 H), 3.19 (m, 2 H), 3.37 (m, 1 H), 3.66 (d, J=9.16 Hz, 1 H), 3.74 (m, 2 H), 3.87 (s, 3 H); 3.98 (m, 1 H), 4.10 (m, 1 H), 4.14 (m, 1 H), 7.08 (m, 2 H), 7.17 (m, 5 H), 7.76 (m, 2 H), 7.93 (d, J=9.49 Hz, 1 H) Example 597 Η NMR (300 MHz, CD3OD) δ ppm 0.78 (d, J=6.44 Hz, 6 H), 0.86 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 2.02 (m, 2 H), 2.53 (dd, J=13.73, 11.36 Hz, 1 H), 2.67 (m, 1 H), 2.81 (s, 3 H), 2.88 (dd, J=13.73, 6.95 Hz, 1 H), 2.97 (dd, J=14.58, 8.14 Hz, 1 H), 3.05 (m, 1 H), 3.14 (m, 2 H), 3.24 (m, 2 H), 3.27 (s„ 2 H), 3.43 (dd, J=14.75, 3.90 Hz, 1 H), 3.72 (d, J=11.19 Hz, 1 H), 3.78 (m, 1 H), 3.87 (s, 2 H), 4.16 (d, J=10.85 Hz, 1 H), 4.37 (d, J=15.60 Hz, 1 H), 4.55 (s, 1 H), 4.64 (m, 1 H), 4.80 (s, 2 H), 7.07 (m, 2 H), 7.17 (m, 4 H), 7.51 (s, 1 H), 7.76 (m, 2 H), 7.93 (d, J=10.17 Hz, 1 H) Example 598 Η NMR (300 MHz, DMSO-d6) δ ppm 0.68 (d, J=6.44 Hz, 3 H), 0.71 (d, J=6.78 Hz, 3 H), 0.80 (d, J=3.05 Hz, 3 H), 0.82 (d, J=3.05 Hz, 3 H), 0.87 (m, 1 H), 1.96 (d, J=7.12 Hz, 2 H), 2.22 (s, 1 H), 2.34 (s, 3 H), 2.43 (d, J=12.89 Hz, 1 H), 2.80 (dd, J=13.73, 6.61 Hz, 1 H), 2.95 (m, 3 H), 3.59 (s, 1 H), 3.76 (d, J=10.85 Hz, 1 H), 3.83 (s, 3 H), 3.90 (d, J=8.14 Hz, 1 H), 4.40 (d, J=5.09 Hz, 1 H), 4.47 (s, 2 H), 4.93 (d, J=6.44 Hz, 1 H), 7.06 (m, 7 H), 7.37 (s, 1 H), 7.64 (s, 1 H), 7.72 (d, J=8.82 Hz, 2 H), 7.87 (d, J=9.49 Hz, 1 H) Example 599
Η NMR (300 MHz, CD3OD) δ ppm 0.75 (d, J=6.44 Hz, 3 H), 0.85 (t, J=7.29 Hz, 3 H), 0.98 (d, J=6.44 Hz, 1 H), 1.18 (s, 1 H), 1.33 (m, 3 H), 1.55 (s, 4 H), 1.71 (s, 2 H), 1.85 (s, 1 H), 2.25 (m, 1 H), 2.54 (dd, J=13.73, 11.36 Hz, 1 H), 2.71 (m, 1 H), 2.99 (m, 1 H), 3.05 (m, 1 H), 3.12 (d, J=8.82 Hz, 2 H), 3.17 (d, J=4.75 Hz, 2 H), 3.23 (m, 2 H), 3.45 (dd, J=14.75, 4.24 Hz,
1 H), 3.80 (dd, J=6.10, 3.73 Hz, 1 H), 3.83 (d, J=10.85 Hz, 1 H), 3.87 (s, 3 H), 4.18 (s, 1 H), 4.36 (d, J=15.60 Hz, 1 H), 4.47 (s, 2 H), 4.63 (m, 1 H), 7.08 (m, 2 H), 7.13 (d, J=6.10 Hz, 3 H), 7.20 (m, 2 H), 7.48 (s, 1 H), 7.77 (m, 2 H) Example 600
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.83 (m, 6 H), 0.87 (d, J=3.73 Hz, 3 H), 0.95 (m, 1 H), 1.28 (s, 1 H), 1.90 (m, 3 H), 3.82 (d, J=10.85 Hz, 1 H), 3.86 (s, 3 H), 4.27 (m, J=15.26 Hz, 2 H), 4.44 ( , 1 H), 5.41 (s, 1 H), 6.72 (d, J=8.82 Hz, 1 H), 6.96 (d, J=8.82 Hz, 2 H), 7.11 (m, 3 H), 7.18 (m, 2 H), 7.32 (d, J=7.46 Hz, 1 H), 7.40 (t, J=7.46 Hz, 1 H), 7.58 (m, 2 H), 7.72 (m, 2 H) Example 601
Η NMR (300 MHz, CDC13) δ ppm 0.90 (d, J=6.78 Hz, 6 H), 1.70 (m, 1 H), 1.87 (dd, J=13.73, 6.95 Hz, 1 H), 2.04 (m, 1 H), 2.37 (m, 1 H), 2.89 (m, 2 H), 2.99 (m, 1 H), 3.12 (m, 2 H), 3.17 (m, 2 H), 3.25 (m, 1 H), 3.45 (m, 1 H), 3.62 (m, 1 H), 3.79 (s, 3 H), 3.87 (s, 3 H), 3.91 (m, 1 H), 4.31 (m, 1 H), 4.54 (m, 2 H), 4.78 (d, J=15.60 Hz, 1 H), 6.75 (d, J=8.82 Hz, 1 H), 7.00 (m, 2 H), 7.12 (m, 1 H), 7.19 (m, 6 H), 7.32 (m, 2 H), 7.74 (m, 3 H) Example 603
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.78 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.82 (m, 1 H), 2.08 (m, 1 H), 2.25 (d, J=6.44 Hz, 2 H), 2.66 (dd, J=13.90, 10.85 Hz, 1 H), 2.78 (dd, J=13.39, 6.61 Hz, 1 H), 2.95 (dd,
J=12.89, 2.03 Hz, 1 H), 3.08 (m, 1 H), 3.22 (m, 1 H), 3.45 (s, 3 H), 3.58 (d, J=17.97 Hz, 1 H), 3.81 (m, 1 H), 3.88 (s, 3 H), 3.88 (m, 1 H), 4.23 (m, 1 H), 4.69 (m, 2 H), 4.76 (d, J=7.12 Hz,
2 H), 6.22 (d, J=9.16 Hz, 1 H), 6.98 (m, 2 H), 7.09 (m, 5 H), 7.19 (s, 1 H), 7.72 (m, 2 H) Example 604 Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.78 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.94 (m, 3 H), 1.81 (m, 1 H), 2.04 (d, J=3.39 Hz, 1 H), 2.05 (m, 1 H), 2.63 (dd, J=14.07, 10.68 Hz, 1 H), 2.77 (dd, J=13.56, 6.44 Hz, 1 H), 2.91 (d, J=2.71 Hz, 1 H), 2.99 (m, 2 H), 3.06 (m, 1 H), 3.18 (m, 2 H), 3.53 (d, J=17.97 Hz, 1 H), 3.80 (m, 2 H), 3.88 (s, 3 H), 4.22 (m, 1 H), 4.62 (m, 2 H), 6.05 (d, J=9.49 Hz, 1 H), 6.97 (s, 1 H), 6.98 (m, 5 H), 7.05 (m, 2 H), 7.33 (m, 1 H), 7.42 (m, 1 H), 7.72 (m, 2 H) Example 605 Η NMR (300 MHz, CDC13) δ ppm 0.83 (d, J=6.44 Hz, 3 H), 0.86 (d, J=6.78 Hz, 3 H), 0.91 (t, J=6.78 Hz, 6 H), 1.28 (s, 1 H), 1.83 (m, 1 H), 2.15 (m, 1 H), 2.70 (m, 1 H), 2.78 (dd, J=13.39, 6.61 Hz, 1 H), 2.98 (m, 1 H), 3.08 (dd, J=14.24, 4.41 Hz, 1 H), 3.19 (m, 1 H), 3.40 (m, 1 H), 3.74 (d, J=17.97 Hz, 1 H), 3.82 (s, 2 H), 3.88 (s, 3 H), 3.92 (d, J=10.85 Hz, 1 H),
4.25 (m, 1 H), 4.98 (m, 2 H), 6.17 (d, J=9.49 Hz, 1 H), 6.98 (m, 2 H), 7.15 (m, 5 H), 7.33 (d, J=8.48 Hz, 1 H), 7.49 (m, 1 H), 7.65 (m, 1 H), 7.72 (m, 2 H), 7.77 (d, J=7.80 Hz, 1 H), 7.95
(d, J=8.48 Hz, 1 H), 8.13 (d, J=8.48 Hz, 1 H) Example 606
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.80 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (m, 3 H), 1.83 (m, 1 H), 2.08 (m, 1 H), 2.71 (dd, J=13.90, 10.85 Hz, 1 H), 2.81 (m, 1 H), 2.97 (m, 2 H), 3.06 (dd, J=8.31, 3.56 Hz, 1 H), 3.18 (m, 2 H), 3.36 (d, J=17.97 Hz, 1 H), 3.66 (m, 1 H), 3.87 (s, 3 H), 3.88 (s, 3 H), 3.96 (d, J=10.85 Hz, 1 H), 4.28 (m, 1 H), 4.90 (m, 2 H), 6.39 (d, J=9.49 Hz, 1 H), 6.97 (m, 2 H), 7.06 (s, 3 H), 7.17 (m, 3 H),
7.26 (m, 1 H), 7.32 (m, 1 H), 7.72 (m, 3 H) Example 607 Η NMR (300 MHz, CD3OD) δ ppm 0.79 (d, J=6.44 Hz, 6 H), 0.87 (d, J=6.44 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 1.27 (m, 3 H), 2.02 (m, 1 H), 2.47 (dd, J=13.56, 11.53 Hz, 1 H), 2.89 (m, 1 H), 3.02 (m, 3 H), 3.23 (dd, J=13.73, 3.56 Hz, 1 H), 3.40 (dd, J=14.92, 3.73 Hz, 1 H), 3.71 (d, J=17.97 Hz, 2 H), 3.78 (m, 1 H), 3.87 (s, 3 H), 4.01 (d, J=11.19 Hz, 1 H), 4.16 (m, 3 H), 4.32 (m, 1 H), 7.08 (m, 2 H), 7.19 (m, 6 H), 7.77 (m, 2 H), 8.22 (d, J=9.83 Hz, 1 H) Example 608
Η NMR (300 MHz, CDC13) δ ppm 0.84 (m, 9 H), 0.92 (m, 3 H), 1.81 (s, 1 H), 2.11 (s, 1 H),
2.72 (m, 1 H), 2.79 (m, 1 H), 2.88 (s, 1 H), 3.00 (m, 1 H), 3.08 (dd, J=14.24, 4.41 Hz, 1 H), 3.18 (m, 1 H), 3.41 (d, J=17.97 Hz, 1 H), 3.71 (d, J=17.97 Hz, 1 H), 3.81 (s, 1 H), 3.88 (s, 3 H), 3.92 (s, 1 H), 3.96 (s, 3 H), 4.26 (s, 1 H), 4.91 (m, 2 H), 6.20 (d, J=9.16 Hz, 1 H), 6.98 (m, 2 H), 7.16 (m, 5 H), 7.72 (m, 2 H), 7.94 (dd, J=8.14, 1.36 Hz, 1 H), 8.02 (s, 1 H), 8.36
(dd, J=4.75, 1.36 Hz, 1 H)
Example 609
Η NMR (300 MHz, CD3OD) δ ppm 0.80 (d, J=6.78 Hz, 3 H), 0.86 (dd, J=6.44, 1.70 Hz, 6
H), 0.90 (d, J=6.44 Hz, 3 H), 2.04 (m, 2 H), 2.49 (dd, J=13.73, 11.70 Hz, 1 H), 2.86 (s, 2 H), 3.03 (m, 1 H), 3.12 (d, J=17.97 Hz, 1 H), 3.23 (dd, J=13.73, 3.56 Hz, 1 H), 3.41 (dd, J=14.92,
3.73 Hz, 1 H), 3.78 (m, 2 H), 3.87 (s, 3 H), 3.92 (s, 3 H), 4.03 (d, J=11.19 Hz, 1 H), 4.15 (m, 1 H), 4.95 (m, 2 H), 7.04 (m, 5 H), 7.17 (m, 2 H), 7.25 (d, J=2.71 Hz, 1 H), 7.35 (dd, J=9.32, 2.88 Hz, 1 H), 7.41 (d, J=8.82 Hz, 1 H), 7.76 (m, 2 H), 7.84 (d, J=9.16 Hz, 1 H), 7.97 (s, 1 H), 8.20 (d, J=8.48 Hz, 1 H) Example 610
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.78 Hz, 3 H), 0.86 (m, 6 H), 0.93 (d, J=6.44 Hz, 3 H), 1.82 (m, 1 H), 2.09 (m, 1 H), 2.67 (dd, J=14.24, 10.85 Hz, 1 H), 2.78 (dd, J=13.56, 6.44 Hz, 1 H), 2.95 (s, 2 H), 3.04 (m, 1 H), 3.19 (m, 1 H), 3.35 (d, J=17.97 Hz, 1 H), 3.64 (m, 1 H), 3.75 (m, 1 H), 3.81 (m, 1 H), 3.88 (s, 3 H), 4.26 (m, 1 H), 5.11 (m, 2 H), 6.12 (d, J=9.16 Hz, 1 H), 6.99 (d, J=8.82 Hz, 2 H), 7.06 (m, 5 H), 7.37 (d, J=2.71 Hz, 1 H), 7.68 (m, 1 H), 7.72 (d, J=9.16 Hz, 2 H), 7.76 (m, 1 H), 8.02 (s, 1 H), 8.19 (d, J=8.14 Hz, 1 H), 8.30 (d, J=8.14 Hz, 1 H), 8.88 (d, J=4.07 Hz, 1 H) Example 611
Η NMR (300 MHz, CD3OD) δ ppm 0.82 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.44 Hz, 6 H), 2.07 (m, 2 H), 2.51 (dd, J=13.56, 11.53 Hz, 1 H), 2.91 (m, 2 H), 3.03 (m, 1 H), 3.18 (d, J=18.31 Hz, 1 H), 3.26 (d, J=3.39 Hz, 1 H), 3.42 (dd, J=14.75, 3.56 Hz, 1 H), 3.79 (m, 2 H), 3.87 (d, J=18.31 Hz, 1 H), 3.87 (s, 3 H), 4.04 (d, J=11.19 Hz, 1 H), 4.16 (m, 1 H), 5.06 (m, 2 H), 7.07 (m, 2 H), 7.16 (m, 5 H), 7.67 (d, J=8.48 Hz, 1 H), 7.76 (m, 2 H), 8.06 (d, J=9.49 Hz, 1 H), 8.45 (dd, J=9.32, 2.54 Hz, 1 H), 8.54 (d, J=8.48 Hz, 1 H), 8.91 (d, J=2.71 Hz, 1 H) Example 612 Η NMR (300 MHz, CDC13) δ ppm 0.80 (d, J=6.44 Hz, 3 H), 0.85 (d, J=6.44 Hz, 6 H), 0.92 (t, J=5.93 Hz, 3 H), 0.90 (m, 2 H), 1.83 (m, 1 H), 2.15 (m, 1 H), 2.71 (m, 1 H), 2.79 (dd, J=13.39, 6.61 Hz, 1 H), 2.98 (m, 2 H), 3.08 (dd, J=13.73, 4.24 Hz, 1 H), 3.18 (m, 1 H), 3.42 (d, J=17.63 Hz, 1 H), 3.71 (d, J=17.63 Hz, 1 H), 3.87 (s, 3 H), 3.95 (d, J=10.85 Hz, 1 H), 4.26 (s, 1 H), 4.96 (m, 2 H), 6.33 (s, 1 H), 6.88 (m, 1 H), 6.97 (m, 2 H), 7.15 (s, 5 H), 7.24 (d, J=3.39 Hz, 1 H), 7.71 (m, 2 H), 7.90 (d, J=15.26 Hz, 2 H) Example 613
Η NMR (300 MHz, CDC13) δ ppm 0.70 (d, J=6.78 Hz, 3 H), 0.75 (d, J=6.78 Hz, 3 H), 0.87 (d, J=3.39 Hz, 3 H), 0.89 (d, J=3.39 Hz, 3 H), 1.89 (m, 1 H), 2.05 (m, 1 H), 2.21 (s, 3 H), 2.24 (s, 1 H), 2.76 (dd, J=13.90, 10.85 Hz, 1 H), 2.88 (s, 1 H), 2.94 (m, 1 H), 2.99 (d, J=4.07 Hz, 1 H), 3.01 (d, J=9.16 Hz, 1 H), 3.07 (m, 2 H), 3.62 (q, J=17.97 Hz, 2 H), 3.88 (s, 3 H), 4.10 (m, 2 H), 4.23 (d, J=9.16 Hz, 1 H), 4.74 (m, 2 H), 6.83 (s, 1 H), 6.99 (m, 2 H), 7.11 (m, 5 H), 7.74 (m, 2 H) Example 614 Η NMR (300 MHz, DMSO-d6) δ ppm 0.64 (d, J=6.78 Hz, 3 H), 0.78 (m, 6 H), 0.82 (d, J=4.07 Hz, 3 H), 1.20 (s, 1 H), 1.72 (s, 1 H), 1.92 (m, 1 H), 2.10 (s, 3 H), 2.38 (dd, J=13.22, 11.53 Hz, 1 H), 2.73 (s, 1 H), 2.79 (dd, J=13.39, 6.61 Hz, 1 H), 2.89 (s, 1 H), 2.93 (m, 1 H), 3.05 (m, 1 H), 3.09 (m, 1 H), 3.20 (m, J=3.05 Hz, 1 H), 3.59 (s, 1 H), 3.76 (d, J=17.97 Hz, 1 H), 3.84 (s, 3 H), 3.94 (d, J=8.82 Hz, 1 H), 4.08 (d, J=10.85 Hz, 1 H), 4.55 (d, J=15.94 Hz, 2 H), 4.97 (d, J=6.44 Hz, 1 H), 6.90 (s, 1 H), 7.01 (m, 5 H), 7.10 (m, 2 H), 7.72 (d, J=8.82 Hz, 2 H), 8.19 (d, J=9.49 Hz, I H) Example 615 Η NMR (300 MHz, CD3OD) δ ppm 0.76 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.44 Hz, 6 H), 0.90 (d, J=6.44 Hz, 3 H), 1.01 (m, 1 H), 1.40 (m, 1 H), 1.88 (m, 1 H), 2.00 (m, 1 H), 2.48 (dd, J=13.56, 11.53 Hz, 1 H), 2.89 (dd, J=13.73, 6.95 Hz, 1 H), 3.02 (m, 1 H), 3.02 (d, J=7.80 Hz, 2 H), 3.15 (d, J=18.31 Hz, 1 H), 3.22 (dd, J=13.56, 3.39 Hz, 1 H), 3.41 (dd, J=14.58, 3.73 Hz,
1 H), 3.77 (m, 2 H), 3.87 (s, 3 H), 4.12 (m, 1 H), 4.18 (m, 1 H), 4.82 (m, 1 H), 4.95 (m, 1 H), 6.93 (d, J=2.71 Hz, 1 H), 7.03 (m, 6 H), 7.16 (m, 1 H), 7.21 (dd, J=8.99, 2.54 Hz, 1 H), 7.28
(d, J=8.48 Hz, 1 H), 7.70 (d, J=9.16 Hz, 1 H), 7.76 (m, 2 H), 7.96 (d, J=8.48 Hz, 1 H) Example 616
Η NMR (300 MHz, CDC13) δ ppm 0.82 (m, 6 H), 0.87 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.22 (m, 1 H), 1.82 (m, 2 H), 2.67 (dd, J=14.24, 10.51 Hz, 1 H), 2.78 (dd, J=13.39, 6.27 Hz, 1 H), 2.97 (m, 3 H), 3.05 (dd, J=9.32, 4.92 Hz, 1 H), 3.19 (m, 1 H), 3.37 (d, J=17.97 Hz, 1 H), 3.61 (m, 1 H), 3.74 (d, J=2.71 Hz, 1 H), 3.83 (m, 1 H), 3.88 (s, 3 H), 3.98 (d, J=11.19 Hz, 1 H), 4.26 (m, 1 H), 5.08 (m, 2 H), 6.12 (d, J=9.16 Hz, 1 H), 6.99 (m, 2 H), 7.05 (m, 6 H), 7.35 (d, J=4.41 Hz, 1 H), 7.64 (m, 1 H), 7.72 (d, J=9.16 Hz, 2 H), 7.77 (m, 1 H), 8.16 (d, J=8.14 Hz, 1 H), 8.29 (d, J=7.80 Hz, 1 H) Example 617
Η NMR (300 MHz, CD3OD) δ ppm 0.75 (d, J=6.44 Hz, 3 H), 0.83 (t, J=7.29 Hz, 3 H), 0.96 (m, 1 H), 1.18 (m, 1 H), 1.55 (m, 6 H), 1.70 (m, 3 H), 1.82 (m, 1 H), 2.24 (m, 1 H), 2.47 (dd, J=13.56, 11.87 Hz, 1 H), 2.95 (m, 2 H), 3.04 (m, 2 H), 3.15 (d, J=8.48 Hz, 1 H), 3.22 (m, 2 H), 3.41 (d, J=4.07 Hz, 1 H), 3.43 (s, 3 H), 3.45 (m, 1 H), 3.66 (m, 1 H), 3.80 (m, 1 H), 4.11 (m, 1 H), 4.18 (m, 1 H), 4.66 (s, 2 H), 4.77 (d, J=6.78 Hz, 2 H), 6.99 (m, 3 H), 7.08 (m, 2 H), 7.12 (m, 2 H), 7.41 (s, 1 H), 7.77 (m, 2 H) Example 618
ΗNMR (300 MHz, CD3OD) δ ppm 0.74 (d, J=6.78 Hz, 3 H), 0.83 (m, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 0.97 (m, 1 H), 1.29 (m, 1 H), 1.80 (dd, J=11.19, 3.39 Hz, 1 H), 2.00 (m, 1 H), 2.46 (dd, J=13.73, 11.70 Hz, 1 H), 2.89 (m, 1 H), 2.94 (m, 1 H), 3.00 (m,
2 H), 3.06 (m, 1 H), 3.22 (dd, J=13.56, 3.39 Hz, 1 H), 3.41 (m, 1 H), 3.43 (s, 2 H), 3.66 (d, J=17.97 Hz, 1 H), 3.77 (m, 1 H), 3.87 (s, 3 H),-4.10 (m, 1 H), 4.66 (s, 2 H), 4.77 (m, 2 H), 4.78 (m, 2 H), 6.99 (m, 3 H), 7.08 (m, 2 H), 7.12 (m, 2 H), 7.41 (s, 1 H), 7.77 (m, 2 H), 8.20 (d, J=9.83 Hz, 1 H) Example 619
Η NMR (300 MHz, CD3OD) δ ppm 0.70 (d, J=6.78 Hz, 3 H), 0.83 (t, J=7.29 Hz, 3 H), 0.98 (m, 9 H), 1.28 (m, 1 H), 1.78 (m, 1 H), 2.44 (dd, J=13.90, 11.53 Hz, 1 H), 2.95 (dd, J=17.97, 3.39 Hz, 2 H), 3.09 (m, 1 H), 3.15 (dd, J=10.17, 5.09 Hz, 2 H), 3.36 (m, 1 H), 3.43 (s, 2 H), 3.65 (m, 1 H), 3.85 (d, J=8.82 Hz, 1 H), 3.88 (m, 3 H), 3.94 (m, 1 H), 4.07 (m, 2 H), 4.66 (s, 2 H), 4.76 (d, J=6.44 Hz, 2 H), 4.80 (s, 2 H), 6.98 (m, 3 H), 7.08 (m, 4 H), 7.41 (s, 1 H), 7.79 (m, 2 H) Example 620
Η NMR (300 MHz, DMSO-d6) δ ppm 0.68 (d, J=6.78 Hz, 3 H), 0.69 (dd, J=9.16, 6.78 Hz, 3 H), 0.80 (d, J=3.39 Hz, 3 H), 0.81 (m, 3 H), 0.84 (d, J=6.78 Hz, 6 H), 1.68 (m, 1 H), 1.91 (m,
1 H), 2.38 (dd, J=13.05, 11.36 Hz, 1 H), 2.76 (m, 1 H), 2.91 (m, 5 H), 2.99 (m, 1 H), 3.07 (m,
2 H), 3.22 (m, 1 H), 3.57 (m, 1 H), 3.74 (d, J=18.31 Hz, 1 H), 3.84 (s, 2 H), 4.03 (m, 2 H), 4.98 (d, J=6.44 Hz, 1 H), 6.99 (m, 1 H), 7.10 (m, 7 H), 7.72 (d, J=8.82 Hz, 1 H), 8.06 (m, 1
H), 8.19 (d, J=9.83 Hz, I H)
Example 621
Η NMR (300 MHz, DMSO-d6) δ ppm 0.69 (dd, J=9.16, 6.78 Hz, 6 H), 0.81 (m, 6 H), 0.84
(d, J=6.78 Hz, 6 H), 1.68 (m, 1 H), 1.92 (m, 2 H), 2.38 (dd, J=13.05, 11.36 Hz, 1 H), 2.77 (m, 1 H), 2.83 (m, 2 H), 2.93 (m, 5 H), 3.07 (m, 2 H), 3.21 (dd, J=14.24, 2.71 Hz, 1 H), 3.59 (d, J=6.44 Hz, 1 H), 3.74 (d, J=18.31 Hz, 1 H), 3.84 (s, 2 H), 4.03 (m, 2 H), 4.98 (d, J=6.44 Hz, 1 H), 7.00 (dd, J=8.99, 4.58 Hz, 1 H), 7.10 (m, 7 H), 7.72 (d, J=8.82 Hz, 2 H) Example 622 Η NMR (300 MHz, DMSO-d6) δ ppm 0.69 (m, 6 H), 0.81 (dd, J=6.78, 2.71 Hz, 6 H), 1.93 (m, 1 H), 2.37 (dd, J=13.22, 11.19 Hz, 1 H), 2.79 (m, 1 H), 2.83 (s, 3 H), 2.93 (m, 1 H), 3.05 (s, 3 H), 3.08 (m, 1 H), 3.21 (dd, J=14.24, 3.05 Hz, 1 H), 3.59 (t, J=6.44 Hz, 1 H), 3.73 (d, J=18.31 Hz, 1 H), 3.84 (s, 3 H), 3.91 (d, J=9.49 Hz, 1 H), 3.99 (d, J=10.85 Hz, 1 H), 4.31 (m, 2 H), 7.00 (m, 1 H), 7.11 (m, 7 H), 7.71 (m, 2 H), 8.21 (d, J=9.49 Hz, 1 H) Example 623 Η NMR (300 MHz, DMSO-d6) δ ppm 0.69 (t, J=6.78 Hz, 6 H), 0.81 (dd, J=6.61, 2.88 Hz, 6 H), 1.93 (m, 2 H), 2.37 (dd, J=13.05, 11.36 Hz, 1 H), 2.80 (dd, J=13.56, 6.44 Hz, 1 H), 2.94 (m, 3 H), 3.07 (dd, J=13.05, 2.88 Hz, 1 H), 3.21 (dd, J=14.24, 3.05 Hz, 1 H), 3.43 (d, J=4.41 Hz, 2 H), 3.57 (m, J=3.73 Hz, 4 H), 3.63 (d, J=4.41 Hz, 2 H), 3.74 (d, J=17.97 Hz, 1 H), 3.84 (s, 3 H), 3.91 (d, J=9.83 Hz, 1 H), 3.99 (d, J=11.19 Hz, 1 H), 4.35 (m, 2 H), 7.00 (m, 1 H), 7.11 (m, 7 H), 7.72 (d, J=8.82 Hz, 2 H), 8.21 (d, J=9.49 Hz, 1 H) Example 624
Η NMR (300 MHz, DMSO-d6) δ ppm 0.69 (d, J=6.44 Hz, 3 H), 0.73 (d, J=6.44 Hz, 3 H), 0.81 (dd, J=6.44, 3.73 Hz, 6 H), 1.94 (m, 2 H), 2.40 (dd, J=13.22, 11.19 Hz, 1 H), 2.80 (dd, J=13.56, 6.44 Hz, 1 H), 2.93 (m, 2 H), 3.06 (m, 2 H), 3.22 (dd, J=14.07, 3.22 Hz, 1 H), 3.58 (m, 1 H), 3.82 (m, 1 H), 3.84 (s, 3 H), 3.91 (m, 1 H), 4.01 (d, J=10.85 Hz, 1 H), 4.27 (m, 2 H), 4.99 (d, J=6.44 Hz, 1 H), 7.01 (m, 1 H), 7.10 (m, 8 H), 7.32 (t, J=7.80 Hz, 2 H), 7.56 (d, J=7.46 Hz, 2 H), 7.71 (m, 2 H) Example 650
Η NMR (300 MHz, DMSO-d6) δ ppm 0.70 (dd, J=6.61, 4.58 Hz, 6 H), 0.80 (dd, J=6.61,
4.58 Hz, 6 H), 1.94 (m, 2 H), 2.42 (dd, J=13.56, 11.19 Hz, 1 H), 2.63 (s, 3 H), 2.71 (m, 1 H),
2.83 (m, 2 H), 3.00 (m, 3 H), 3.18 (m, 2 H), 3.61 (m, 1 H), 3.76 (d, J=10.85 Hz, 1 H), 3.92 (m, 1 H), 4.33 (d, J=1.36 Hz, 2 H), 4.86 (d, J=6.10 Hz, 1 H), 5.94 (s, 2 H), 6.60 (d, J=8.82
Hz, 2 H), 7.07 (m, 5 H), 7.21 (d, J=3.73 Hz, 1 H), 7.39 (d, J=8.82 Hz, 2 H), 7.84 (d, J=9.49 Hz, l H) Example 651
Η NMR (300 MHz, DMSO-d6) δ ppm 0.69 (dd, J=9.32, 6.61 Hz, 6 H), 0.82 (dd, J=6.78, 1.36 Hz, 6 H), 1.94 (m, 2 H), 2.42 (dd, J=13.56, 10.85 Hz, 1 H), 2.63 (d, J=2.37 Hz, 3 H),
2.84 (m, 2 H), 2.98 (m, 3 H), 3.13 (m, 1 H), 3.22 (dd, J=14.58, 3.39 Hz, 1 H), 3.59 (d, J=5.76 Hz, 1 H), 3.75 (d, J=10.51 Hz, 1 H), 3.91 (m, 1 H), 4.34 (m, 3 H), 4.95 (d, J=6.10 Hz, 1 H), 5.81 (s, 2 H), 6.86 (d, J=2.03 Hz, 1 H), 6.89 (d, J=2.37 Hz, 1 H), 7.06 (m, 6 H), 7.36 (d, L 8.48 Hz, 1 H), 7.85 (d, J=9.49 Hz, 1 H) Example 652
Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.80 (d, J=6.78 Hz, 3 H), 0.90 (m, 6 H), 1.87 (m, 1 H), 2.13 (m, 1 H), 2.65 (m, 1 H), 2.69 (s, 3 H), 2.78 (m, 2 H), 2.93 (dd, J=7.63, 2.88 Hz, 2 H), 3.04 (d, J=3.39 Hz, 2 H), 3.10 (m, 1 H), 3.16 (dd, J=9.16, 4.07 Hz, 1 H), 3.24 (m, 2 H), 3.59 (d, J=11.19 Hz, 1 H), 3.78 (m, 1 H), 4.04 (m, 1 H), 4.42 (s, 2 H), 6.46 (d, J=8.82 Hz, 1 H), 6.92 (m, 2 H), 6.96 (s, 1 H), 7.15 (m, 5 H), 7.64 (m, 2 H) Example 653
Η NMR (300 MHz, DMSO-d6) δ ppm 0.67 (d, J=6.78 Hz, 3 H), 0.70 (d, J=6.78 Hz, 3 H), 0.79 (d, J=3.39 Hz, 3 H), 0.81 (d, J=3.39 Hz, 3 H), 1.32 (m, 6 H), 1.93 (m, 2 H), 2.40 (dd, J=13.39, 11.02 Hz, 1 H), 2.77 (dd, J=13.73, 6.61 Hz, 2 H), 2.88 (m, 3 H), 2.99 (m, 2 H), 3.15 (m, 1 H), 3.23 (m, 1 H), 3.60 (m, 1 H), 3.75 (d, J=10.85 Hz, 1 H), 3.88 (m, 1 H), 4.02 (s, 1 H), 4.35 (m, 2 H), 4.91 (d, J=6.44 Hz, 1 H), 6.88 (d, J=8.82 Hz, 2 H), 7.06 (m, 6 H), 7.59 (d, J=8.82 Hz, 2 H), 7.85 (d, J=9.49 Hz, 1 H) Example 654 Η NMR (300 MHz, DMSO-d6) δ ppm 0.70 (t, J=6.27 Hz, 6 H), 0.80 (dd, J=6.44, 4.41 Hz, 6 H), 1.32 (m, 6 H), 1.93 (m, 2 H), 2.41 (dd, J=13.56, 10.85 Hz, 1 H), 2.71 (m, 1 H), 2.83 (m, 2 H), 3.01 (m, 2 H), 3.17 (m, 2 H), 3.60 (m, 1 H), 3.76 (d, J=10.85 Hz, 1 H), 3.89 (d, J=10.51 Hz, 1 H), 4.02 (s, 1 H), 4.35 (m, 2 H), 4.87 (d, J=6.10 Hz, 1 H), 5.94 (s, 2 H), 6.60 (d, J=8.82 Hz, 2 H), 7.03 (s, 1 H), 7.08 (m, 5 H), 7.38 (m, 2 H), 7.83 (d, J=9.49 Hz, 1 H) Example 655 Η NMR (300 MHz, DMSO-d6) δ ppm 0.67 (d, J=6.78 Hz, 3 H), 0.70 (m, 3 H), 0.83 (m, 6 H), 1.33 (m, 6 H), 1.96 (s, 1 H), 2.45 (s, 1 H), 2.83 (m, 2 H), 3.00 (m, 4 H), 3.22 (m, 4 H), 3.75 (d, J=10.85 Hz, 1 H), 3.92 (s, 2 H), 4.35 (m, 2 H), 4.99 (m, 1 H), 5.81 (s, 1 H), 6.86 (d, J=2.03 Hz, 1 H), 6.89 (m, 1 H), 7.05 (m, 5 H), 7.21 (s, 1 H), 7.23 (m, 1 H), 7.35 (d, J=8.48 Hz, 1 H), 7.84 (d, J=9.83 Hz, 1 H) Example 656
Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.80 (d, J=6.78 Hz, 3 H), 0.90 (dd, J=8.48, 6.78 Hz, 6 H), 1.38 (t, J=7.29 Hz, 3 H), 1.68 (s, 2 H), 1.87 (m, 2 H), 2.12 (s, 1 H), 2.70 (d, J=14.92 Hz, 1 H), 2.83 (s, 1 H), 2.93 (dd, J=7.29, 4.58 Hz, 3 H), 3.04 (s, 2 H), 3.11 (d, J=8.14 Hz, 3 H), 3.24 (d, J=8.48 Hz, 2 H), 3.58 (s, 1 H), 3.77 (s, 1 H), 4.06 (s, 1 H), 4.42 (s, 1 H), 6.92 (d, J=8.82 Hz, 2 H), 7.00 (s, 1 H), 7.15 (m, 5 H), 7.65 (d, J=8.48 Hz, 2 H) Example 657 Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.38 (m, 3 H), 1.82 (m, 1 H), 2.12 (m, 1 H), 2.67 (m, 1 H), 2.71 (m, 1 H), 2.77 (m, 1 H), 2.94 (m, 1 H), 3.00 (m, 2 H), 3.17 (m, 2 H), 3.24 (d, J=8.82 Hz, 1 H), 3.65 (d, J=11.19 Hz, 1 H), 3.74 (m, 1 H), 3.89 (m, 1 H), 4.12 (s, 2 H), 4.18 (m, 1 H), 4.43 (m, 2 H), 4.52 (d, J=8.14 Hz, 1 H), 4.65 (d, J=10.51 Hz, 1 H), 6.38 (d, J=9.16 Hz, 1 H), 6.67 (m, 2 H), 6.95 (s, 1 H), 7.15 (m, 5 H), 7.57 (m, 2 H) Example 658
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.90 (d, J=3.39 Hz, 3 H), 0.92 (d, J=3.73 Hz, 3 H), 1.37 (t, J=7.63 Hz, 3 H), 1.87 (m, 1 H), 2.17 (m, 1 H), 2.65 (q, J=8.36 Hz, 1 H), 2.78 (dd, J=14.24, 10.51 Hz, 1 H), 2.90 (dd, J=7.46, 4.41 Hz, 2 H), 3.00 (m, 2 H), 3.12 (m, 2 H), 3.23 (m, 1 H), 3.72 (d, J=3.73 Hz, 1 H), 3.76 (d,
J=10.17 Hz, 1 H), 3.83 (m, 1 H), 4.24 (m, 1 H), 4.42 (m, 2 H), 4.57 (d, J=6.78 Hz, 2 H), 6.58 (d, J=8.82 Hz, 1 H), 6.94 (s, 1 H), 7.01 (d, J=2.03 Hz, 1 H), 7.04 (t, J=2.54 Hz, 1 H), 7.17 (m, 7 H), 7.35 (m, 1 H) Example 659 Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.78 Hz, 3 H), 0.80 (d, J=6.78 Hz, 3 H), 0.90 (m, 3 H), 0.93 (d, J=3.05 Hz, 3 H), 1.38 (t, J=7.63 Hz, 3 H), 1.88 (m, 1 H), 2.13 (m, 1 H), 2.74 (m, 2 H), 2.79 (m, 1 H), 2.94 (m, 1 H), 3.01 (m, 2 H), 3.05 (d, J=4.07 Hz, 2 H), 3.14 (m, 1 H), 3.23 (m, 2 H), 3.62 (m, 1 H), 3.77 (m, 2 H), 4.06 (m, 1 H), 4.43 (d, J=2.37 Hz, 2 H), 6.42 (d, J=8.82 Hz, 1 H), 6.81 (d, J=8.48 Hz, 1 H), 6.98 (s, 1 H), 7.01 (d, J=2.37 Hz, 1 H), 7.04 (d, J=2.37 Hz, 1 H), 7.11 (d, J=2.03 Hz, 2 H), 7.15 (m, 5 H) Example 660
Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.80 (d, J=6.44 Hz, 3 H), 0.90 (m, 6 H), 1.86 (m, 1 H), 2.11 (m, 1 H), 2.69 (dd, J=14.24, 10.17 Hz, 1 H), 2.79 (m, 1 H), 2.93 (m, 1 H), 3.03 (m, 2 H), 3.12 (m, 3 H), 3.23 (m, 2 H), 3.48 (s, 3 H), 3.61 (d, J=10.85 Hz, 1 H), 3.77 (m, 2 H), 4.11 (m, 1 H), 4.47 (m, 2 H), 4.70 (s, 2 H), 6.51 (d, J=9.16 Hz, 1 H), 6.92 (m, 2 H), 7.12 (s, 1 H), 7.17 (m, 5 H), 7.65 (m, 2 H) Example 661
Η NMR (300 MHz, CDC13) δ ppm 0.80 (m, 6 H), 0.86 (m, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.82 (dd, J=8.31, 6.61 Hz, 1 H), 2.13 (m, 1 H), 2.71 (m, 2 H), 2.77 (m, 1 H), 2.93 (m, 1 H), 2.97 (m, 2 H), 3.11 (m, 4 H), 3.21 (m, 1 H), 3.48 (d, J=3.73 Hz, 3 H), 3.65 (d, J=10.85 Hz, 1 H), 3.74 (d, J=12.55 Hz, 1 H), 4.17 (m, 2 H), 4.45 (q, J=15.26 Hz, 2 H), 4.70 (s, 2 H), 6.39 (d, J=8.82 Hz, 1 H), 6.67 (m, 2 H), 7.09 (d, J=3.73 Hz, 1 H), 7.16 (m, 5 H), 7.56 (m, 2 H) Example 662
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.90 (d, J=3.39 Hz, 3 H), 0.92 (d, J=3.39 Hz, 3 H), 1.85 (m, 1 H), 2.18 (m, 1 H), 2.67 (q, J=8.48 Hz, 1 H), 2.79 (dd, J=14.41, 10.34 Hz, 1 H), 2.90 (dd, J=7.46, 3.73 Hz, 2 H), 3.04 (m, 1 H), 3.14 (m, 2 H), 3.23 (m, 1 H), 3.48 (s, 3 H), 3.72 (d, J=4.07 Hz, 1 H), 3.76 (d, J=10.17 Hz, 1 H), 3.82 (m, 1 H), 4.25 (m, 1 H), 4.45 (m, 2 H), 4.57 (s, 2 H), 4.70 (s, 2 H), 6.58 (d, J=8.48 Hz, 1 H), 7.01 (d, J=2.37 Hz, 1 H), 7.03 (d, J=2.03 Hz, 1 H), 7.09 (s, 1 H), 7.19 (m, 6 H), 7.35 (m, 1 H) Example 663
Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.78 Hz, 3 H), 0.80 (d, J=6.78 Hz, 3 H), 0.90 (d, J=3.05 Hz, 3 H), 0.93 (d, J=3.39 Hz, 3 H), 1.26 (t, J=7.12 Hz, 3 H), 1.87 (s, 1 H), 2.13 (s, 1 H), 2.71 (s, 1 H), 2.81 (d, J=13.90 Hz, 2 H), 2.92 (t, J=7.12 Hz, 2 H), 3.07 (m, 3 H), 3.21 (m, 2 H), 3.49 (s, 3 H), 3.64 (d, J=10.51 Hz, 1 H), 3.77 (s, 1 H), 4.12 (q, J=7.12 Hz, 2 H), 4.46 (s, 2 H), 4.70 (s, 2 H), 6.39 (s, 1 H), 6.81 (d, J=8.48 Hz, 1 H), 7.02 (m, 1 H), 7.13 (s, 1 H), 7.17 (m, 5 H) Example 664
Η NMR (300 MHz, CD3OD) δ ppm 0.78 (dd, J=6.44, 1.70 Hz, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 2.01 (m, 1 H), 2.46 (s, 1 H), 2.52 (m, 1 H), 2.68 (d, J=7.46 Hz, 1 H), 2.71 (s, 3 H), 2.91 (m, 1 H), 2.99 (m, 2 H), 3.11 (m, 4 H), 3.21 (m, 2 H), 3.43 (dd, J=14.92, 3.73 Hz, 1 H), 3.71 (s, 1 H), 3.72 (d, J=2.71 Hz, 3 H), 3.78 (d, J=11.19 Hz, 1 H), 4.12 (s, 1 H), 4.44 (m, 2 H), 6.88 (d, J=8.48 Hz, 1 H), 7.08 (m, 3 H), 7.16 (m, 2 H), 7.22 (s, 1 H), 7.43 (dd, J=8.48, 2.37 Hz, 1 H), 7.68 (d, J=1.36 Hz, 1 H), 7.75 (s, 1 H), 7.81 (d, J=2.37 Hz, 1 H), 7.91 (d, J=9.49 Hz, 1 H) Example 665
Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.44 Hz, 3 H), 0.83 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.44 Hz, 3 H), 0.91 (m, 3 H), 1.88 (d, J=7.46 Hz, 1 H), 2.17 (d, J=11.53 Hz, 1 H), 2.69 (s, 3 H), 2.74 (m, 1 H), 2.84 (m, 2 H), 2.96 (m, 3 H), 3.15 (m, 5 H), 3.63 (d, J=11.19 Hz, 1 H), 3.77 (s, 1 H), 4.16 (s, 1 H), 4.40 (d, J=2.37 Hz, 2 H), 6.56 (d, J=9.16 Hz, 1 H), 6.93 (s, 1 H), 7.18 (m, 5 H), 7.71 (d, J=3.73 Hz, 1 H), 8.02 (s, 1 H) Example 666 , Η NMR (300 MHz, CD3OD) δ ppm 0.76 (d, J=6.62 Hz, 6 H), 0.86 (t, J=6.62 Hz, 3 H), 0.90 (m, 3 H), 1.29 (s, 1 H), 2.02 (d, J=6.62 Hz, 1 H), 2.47 (dd, J=13.42, 11.21 Hz, 1 H), 2.87 (dd, J=13.97, 6.99 Hz, 2 H), 2.95 (m, 2 H), 3.03 (m, 2 H), 3.07 (m, 2 H), 3.18 (s, 2 H), 3.37 (m, 1 H), 3.70 (m, 1 H), 3.75 (s, 1 H), 4.14 (s, 1 H), 4.31 (d, J=6.62 Hz, 2 H), 4.55 (s, 1 H), 6.91 (m, 1 H), 7.03 (m, 3 H), 7.14 (m, 2 H), 7.32 (m, 1 H), 7.67 (m, 2 H), 7.92 (s, 1 H) Example 667 Η NMR (300 MHz, CD3OD) δ ppm 0.77 (m, 6 H), 0.87 (m, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 1.02 (t, J=7.29 Hz, 1 H), 2.03 (m, 1 H), 2.52 (m, 1 H), 2.71 (m, 3 H), 2.71 (m, 2 H), 2.91 (m, 2 H), 3.01 (m, 2 H), 3.09 (m, 1 H), 3.20 (m, 2 H), 3.41 (dd, J=14.75, 3.56 Hz, 1 H), 3.73 (m, 1 H), 3.78 (m, 1 H), 4.13 (s, 1 H), 4.42 (m, 2 H), 6.81 (m, 1 H), 7.08 (m, 3 H), 7.16 (m, 2 H), 7.23 (m, 1 H), 7.48 (m, 1 H), 7.54 (dd, J=8.14, 5.76 Hz, 1 H), 7.85 (t, J=2.71 Hz, 1 H), 7.96 (d, J=9.83 Hz, 1 H), 8.16 (m, 2 H), 8.71 (dd, J=4.92, 1.53 Hz, 1 H), 8.88 (d, LM2.37 Hz, 1 H) Example 668 Η NMR (300 MHz, CD3OD) δ ppm 0.78 (d, J=6.78 Hz, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 2.02 (m, 2 H), 2.51 ( , 2 H), 2.70 (s, 3 H), 2.93 (dd, J=13.39, 7.29 Hz, 2
\ H), 2.98 (s, 3 H), 3.07 (m, 3 H), 3.14 (m, 2 H), 3.22 (m, 2 H), 3.42 (dd, J=14.75, 3.56 Hz, 1 H), 3.73 (m, 1 H), 3.75 (m, 1 H), 4.10 (s, 1 H), 4.41 (d, J=7.12 Hz, 2 H), 7.01 (m, 1 H), 7.08 (m, 3 H), 7.16 (m, 2 H), 7.21 (s, 1 H), 7.52 (m, 1 H), 7.82,(m, 1 H), 7.91 (d, J=9.49 Hz, 1 H) Example 669 Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, L 6.44 Hz, 3 H), 0.79 (d, J=6.44 Hz, 3 H), 0.88 (m, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 0.99 (m, 2 H), 1.12 (m, 2 H), 1.27 (m, 1 H), 1.86 (dd, J=13.56, 6.78 Hz, 1 H), 2.10 (m, 1 H), 2.30 (m, 1 H), 2.69 (m, 2 H), 2.93 (m, 2 H), 3.06 (dd, J=6.61, 3.56 Hz, 2 H), 3.13 (m, 3 H), 3.23 (m, 2 H), 3.62 (d, J=10.85 Hz, 1 H), 3.78 (m, 2 H), 4.09 (m, 1 H), 4.38 (s, 2 H), 6.57 (d, J=9.16 Hz, 1 H), 6.88 (m, 1 H), 6.93 (m, 1 H), 7.14 (m, 5 H), 7.65 (m, 1 H) Example 670 Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.90 (d, J=4.07 Hz, 3 H), 0.92 (d, J=4.07 Hz, 3 H), 0.99 (m, 3 H), 1.11 (m, 2 H), 1.86 (dd, J=13.39, 6.95 Hz, 1 H), 2.17 (m, 1 H), 2.28 (m, 1 H), 2.64 (q, J=8.48 Hz, 1 H), 2.78 (dd, J=14.24, 10.51 Hz, 1 H), 2.89 (m, 2 H), 3.04 (dd, J=15.26, 8.14 Hz, 1 H), 3.12 (m, 3 H), 3.22 (m, 1 H), 3.74 (m, 2 H), 4.26 (m, 1 H), 4.38 (m, 2 H), 4.57 (s, 1 H), 6.55 (d, J=9.16 Hz, 1 H), 6.83 (s, 1 H), 7.02 (dd, J=8.48, 2.03 Hz, 1 H), 7.17 (m, 7 H), 7.35 (d, J=8.48 Hz, 1 H) Example 671 Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.78 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.00 (m, 2 H), 1.11 (m, 3 H), 1.82 (m, 1 H), 2.13 (m, 1 H), 2.29 (m, 1 H), 2.68 (m, 1 H), 2.75 (m, 2 H), 2.96 (m, 2 H), 3.10 (m, 4 H), 3.21 (m, 1 H), 3.65 (d, J=10.85 Hz, 1 H), 3.74 (s, 1 H), 3.89 (s, 1 H), 4.16 (m, 2 H), 4.38 (m, 2 H), 6.38 (d, J=8.82 Hz, 1 H), 6.68 (m, 2 H), 6.84 (s, 1 H), 7.16 (m, 5 H), 7.56 (m, 2 H) Example 672
Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.23 (t, J=7.63 Hz, 3 H), 1.86 (m, 1 H), 2.12 (m, 1 H), 2.64 (d, J=7.80 Hz, 1 H), 2.69 (m, 3 H), 2.76 (m, 2 H), 2.87 (m, 1 H), 2.97 (m, 1 H), 3.04 (m, 2 H), 3.11 (dd, J=8.48, 3.73 Hz, 2 H), 3.21 (m, 3 H), 3.60 (d, J=10.85 Hz, 1 H), 3.76 (m, 1 H), 4.05 (m, 1 H), 4.41 (s, 2 H), 6.35 (d, J=9.16 Hz, 1 H), 6.84 (m, 1 H), 6.95 (m, 1 H), 7.16 (m, 6 H), 7.47 (dd, J=8.48, 2.37 Hz, 1 H), 7.56 (d, J=2.37 Hz, 1 H) Example 673
Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.44 Hz, 3 H), 0.85 (m, 9 H), 1.87 (s, 1 H), 2.22 (s, 1 H), 2.69 (s, 3 H), 2.76 (s, 1 H), 3.00 (m, 5 H), 3.23 (m, 3 H), 3.32 (s, 2 H), 3.60 (d, J=10.51 Hz, 1 H), 3.85 (s, 1 H), 4.18 (s, 1 H), 4.43 (m, 2 H), 6.80 (s, 1 H), 6.92 (d, J=8.48 Hz, 1 H), 7.19 (m, 5 H), 7.52 (d, J=2.03 Hz, 1 H), 7.56 (d, J=2.37 Hz, 1 H) Example 674
Η NMR (300 MHz, CDC13) δ ppm 0.73 (d, J=6.44 Hz, 3 H), 0.79 (d, J=6.78 Hz, 3 H), 0.89 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.88 (s, 1 H), 2.12 (m, 1 H), 2.28 (s, 3 H), 2.69 (s, 3 H), 2.75 (m, 1 H), 2.92 (m, 2 H), 3.14 (m, 4 H), 3.60 (d, J=10.85 Hz, 1 H), 3.76 (d, J=8.48 Hz, 1 H), 4.06 (s, 1 H), 4.42 (s, 2 H), 6.43 (d, J=8.48 Hz, 1 H), 6.86 (d, J=8.48 Hz, 1 H), 6.95 (s, 1 H), 7.16 (m, 5 H), 7.47 (m, 2 H), 7.55 (d, J=1.70 Hz, 2 H), 7.75 (d, J=8.82 Hz, 1 H), 7.85 (s, 1 H) i
Example 675
Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.44 Hz, 3 H), 0.80 (d, J=6.44 Hz, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 1.88 (d, J=6.78 Hz, 1 H), 2.14 (m, 1 H), 2.69 (s, 3 H), 2.75 (m, 2 H), 2.92 (m, 2 H), 3.00 (m, 2 H), 3.10 (s, 3 H), 3.13 (m, 1 H), 3.22 (m, 2 H), 3.65 (d, J=10.85 Hz, 1 H), 3.78 (d, J=9.83 Hz, 2 H), 4.12 (q, J=7.12 Hz, 1 H), 4.42 (m, 2 H), 6.53 (d, J=8.82 Hz, 1 H), 6.93 (s, 1 H), 7.15 (m, 5 H), 7.33 (d, J=8.82 Hz, 2 H), 7.57 (s, 1 H), 7.77 (d, J=8.82 Hz, 2 H) Example 676 Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.86 (d, J=6.78 Hz, 3 H), 0.88 (m, 3 H), 1.88 (m, 1 H), 2.16 (m, 1 H), 2.49 (s, 3 H), 2.67 (m, 2 H), 2.71 (m, 3 H), 2.89 (m, 1 H), 3.00 (dd, J=14.24, 4.41 Hz, 1 H), 3.14 (d, J=7.46 Hz, 2 H), 3.22 (m, 4 H), 3.49 (s, 1 H), 3.58 (d, J=11.19 Hz, 1 H), 3.67 (d, J=6.44 Hz, 1 H), 3.95 (s, 1 H), 4.42 (m, 2 H), 6.39 (d, J=8.14 Hz, 1 H), 6.87 (d, J=8.14 Hz, 1 H), 6.97 (s, 1 H), 7.17 (m, 5 H), 7.24 (s, 1 H), 7.67 (d, J=10.85 Hz, 1 H) Example 677 Η NMR (300 MHz, CDC13) δ ppm 0.82 (dd, J=10.85, 6.44 Hz, 9 H), 0.88 (m, 3 H), 1.86 (d, J=6.78 Hz, 1 H), 2.17 (m, 1 H), 2.51 (s, 3 H), 2.68 (d, J=3.73 Hz, 3 H), 2.68 (m, 1 H), 2.84 (s, 1 H), 3.04 (m, 1 H), 3.11 (m, 2 H), 3.19 (m, 2 H), 3.25 (m, 2 H), 3.49 (d, J=5.09 Hz, 1 H), 3.61 (d, J=10.85 Hz, 1 H), 3.72 (s, 1 H), 3.82 (d, J=3.39 Hz, 1 H), 4.02 (s, 1 H), 4.41 (d, J=1.70 Hz, 2 H), 6.44 (d, J=8.82 Hz, 1 H), 6.60 (s, 1 H), 6.92 (m, 1 H), 7.17 (m, 5 H), 7.91 (s, I H)
Example 678
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.83 ( , 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.93 (m, 3 H), 1.85 (dd, J=8.48, 6.78 Hz, 1 H), 2.15 (m, 1 H), 2.34 (s, 3 H), 2.69 (s, 3 H), 2.74 (m, 1 H), 2.83 (m, 1 H), 2.97 (m, 2 H), 3.09 (m, 2 H), 3.15 (m, 1 H), 3.22 (m, 2 H), 3.64 (d, J=11.19 Hz, 1 H), 3.74 (dd, J=8.65, 2.88 Hz, 1 H), 3.89 (d, J=3.05 Hz, 1 H), 4.16 (m, 1 H), 4.41 (m, 2 H), 6.11 (s, 1 H), 6.46 (d, J=8.82 Hz, 1 H), 6.92 (d, J=6.44 Hz, 1 H), 7.17 (m, 5 H), 7.48 (d, J=1.70 Hz, 1 H), 7.64 (d, J=2.37 Hz, 1 H) Example 679 Η NMR (300 MHz, CD3OD) δ ppm 0.78 (d, J=6.78 Hz, 6 H), 0.90 (m, 6 H), 2.01 (m, 2 H), 2.46 (m, 1 H), 2.51 (m, 1 H), 2.63 (d, J=3.39 Hz, 3 H), 2.69 (m, 3 H), 2.92 (dd, J=13.56, 7.12 Hz, 2 H), 3.01 (m, 2 H), 3.08 (m, 2 H), 3.15 (m, 1 H), 3.21 (m, 2 H), 3.30 (dd, J=3.05, 1.70 Hz, 2 H), 3.42 (dd, J=14.92, 3.73 Hz, 1 H), 3.74 (m, 2 H), 4.11 (m, 1 H), 4.41 (s, 2 H), 6.94 (d, J=8.48 Hz, 1 H), 7.09 (m, 3 H), 7.15 (m, 2 H), 7.20 (s, 1 H), 7.42 (dd, J=8.65, 2.20 Hz, 1 H), 7.84 (d, J=2.37 Hz, 1 H) Example 680
Η NMR (300 MHz, CD3OD) δ ppm 0.77 (dd, J=6.78, 1.36 Hz, 6 H), 0.89 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 1.32 (m, 3 H), 2.01 (m, 2 H), 2.51 (m, 2 H), 2.69 (s, 3 H), 2.93 (m, 1 H), 2.97 (m, 1 H), 3.06 (m, 2 H), 3.15 (m, 1 H), 3.22 (m, 2 H), 3.29 (m, 2 H), 3.46 (dd, J=14.92, 3.39 Hz, 1 H), 3.73 (m, 2 H), 4.10 (m, 1 H), 4.26 (q, J=7.12 Hz, 2 H), 4.41 (m, 2 H), 6.94 (d, J=8.48 Hz, 1 H), 7.09 (m, 3 H), 7.15 (m, 2 H), 7.18 (s, 1 H), 7.38 (dd, J=8.48, 2.37 Hz, 1 H), 7.91 (m, 1 H), 8.34 (d, J=1.70 Hz, 1 H) Example 681 Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.25 (d, J=6.78 Hz, 6 H), 1.62 (s, 1 H), 1.86 (d, J=6.10 Hz, 1 H), 2.14 (d, J=6.78 Hz, 1 H), 2.72 (s, 3 H), 2.80 (d, J=18.65 Hz, 1 H), 2.89 (m, 1 H), 2.96 (m, 2 H), 3.02 (m, 2 H), 3.11 (m, 2 H), 3.17 (d, J=9.16 Hz, 1 H), 3.26 (m, 2 H), 3.57 (d, J=11.19 Hz, 1 H), 3.77 (d, J=5.43 Hz, 1 H), 3.99 (s, 1 H), 4.43 (s, 2 H), 6.30 (d, J=8.82 Hz, 1 H), 6.84 (d, J=8.48 Hz, 1 H), 6.99 (s, 1 H), 7.18 (m, 5 H), 7.46 (dd, J=8.31, 2.20 Hz, 1 H), 7.60 (d, J=2.37 Hz, 1 H) Example 682 Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.78 (d, J=6.44 Hz, 3 H), 0.90 (d, J=6.78 Hz, 3 H), 0.91 (d, J=2.37 Hz, 3 H), 1.88 (dd, J=14.41, 6.95 Hz, 1 H), 2.13 (m, 1 H), 2.74 (m, 1 H), 2.89 (d, J=7.80 Hz, 1 H), 2.95 (m, 2 H), 3.00 (m, 2 H), 3.05 (dd, J=6.44, 2.71 Hz, 2 H), 3.17 (m, 1 H), 3.25 (m, 1 H), 3.56 (d, J=10.85 Hz, 1 H), 3.74 (s, 1 H), 3.82 (s, 3 H), 3.96 (s, 1 H), 3.99 (d, J=2.37 Hz, 1 H), 4.65 (m, 2 H), 6.42 (d, J=8.48 Hz, 1 H), 6.95 (d, J=8.82 Hz, 2 H), 7.12 (m, 5 H), 7.33 (m, 3 H), 7.63 (d, J=8.82 Hz, 2 H), 7.73 (m, 1 H) Example 683
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.81 (m, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.94 (d, J=6.78 Hz, 3 H), 1.85 (d, J=6.78 Hz, 1 H), 2.13 (m, 1 H), 2.29 (s, 6 H), 2.70 (s, 3 H), 2.73 (d, J=3.05 Hz, 1 H), 2.79 (m, 1 H), 2.96 (d, J=8.14 Hz, 1 H), 3.02 (d,
J=1.36 Hz, 1 H), 3.15 (m, 7 H), 3.63 (d, J=10.85 Hz, 1 H), 3.74 (m, 1 H), 4.16 (d, J=9.16 Hz, 1 H), 4.41 (m, 2 H), 6.38 (d, J=9.49 Hz, 1 H), 6.94 (s, 1 H), 7.16 (m, 5 H), 7.41 (d, J=10.17 Hz, 2 H) Example 684 Η NMR (300 MHz, CDC13) δ ppm 0.82 (dd, J=6.44, 4.41 Hz, 6 H), 0.91 (d, J=3.05 Hz, 3 H), 0.93 (d, J=3.39 Hz, 3 H), 1.55 (s, 1 H), 1.87 (s, 1 H), 2.19 (s, 1 H), 2.81 (s, 1 H), 2.90 (d, J=7.12 Hz, 2 H), 3.05 (s, 2 H), 3.15 (s, 4 H), 3.81 (s, 2 H), 4.17 (s, 1 H), 4.28 (s, 2 H), 4.38 (s, 1 H), 6.52 (s, 1 H), 7.03 (s, 1 H), 7.22 (m, 7 H), 7.35 (m, 2 H), 7.80 (d, J=1.70 Hz, 1 H) Example 685 Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.90 (m, 6 H), 1.84 (m, 1 H), 2.16 (m, 1 H), 2.73 (dd, J=14.41, 10.34 Hz, 1 H), 2.86 (m, 3 H), 3.07 (dd, J=9.66, 3.22 Hz, 2 H), 3.16 (m, 1 H), 3.24 (m, 1 H), 3.31 (t, J=8.99 Hz, 1 H), 3.62 (d, J=10.85 Hz, 1 H), 3.82 (s, 2 H), 4.18 (s, 1 H), 4.41 (d, J=15.94 Hz, 1 H), 4.59 (m, 1 H), 6.50 (d, J=8.82 Hz, 1 H), 6.93 (m, 2 H), 7.18 (m, 6 H), 7.51 (s, 1 H), 7.66 (d, J=8.82 Hz, 2 H) Example 686
Η NMR (300 MHz, CDC13) δ ppm 0.80 (t, J=6.61 Hz, 6 H), 0-90 (d, J=6.44 Hz, 3 H), 0.97 (d, J=6.78 Hz, 3 H), 1.91 (m, 1 H), 2.21 (m, 1 H), 2.66 (m, 2 H), 2.70 (s, 3 H), 2.84 (m, 2 H), 2.94 (d, J=8.48 Hz, 1 H), 3.05 (m, 1 H), 3.13 (m, 1 H), 3.20 (m, 1 H), 3.28 (m, 1 H), 3.39 (s, 1 H), 3.93 (d, J=9.16 Hz, 2 H), 4.32 (m, 1 H), 4.45 (m, 2 H), 6.67 (d, J=7.12 Hz, 1 H), 6.70 (d, J=8.14 Hz, 1 H), 6.96 (d, J=3.05 Hz, 1 H), 7.14 (m, 3 H), 7.19 (m, 7 H) Example 687
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.90 (d, J=3.39 Hz, 3 H), 0.92 (d, J=3.05 Hz, 3 H), 1.86 (m, 1 H), 2.14 (s, 3 H), 2.67 (m, 1 H), 2.79 (dd, J=14.41, 10.68 Hz, 1 H), 2.90 (dd, J=7.46, 4.07 Hz, 2 H), 3.04 (dd, J=15.26, 8.14 Hz, 1 H), 3.11 (dd, J=8.99, 4.24 Hz, 3 H), 3.16 (m, 3 H), 3.23 (m, 2 H), 3.77 (d, J=10.17 Hz, 1 H), 3.83 (m, 1 H), 4.25 (m, 1 H), 4.45 (m, 2 H), 5.34 (s, 2 H), 6.57 (d, J=8.48 Hz, 1 H), 7.01 (d, J=2.03 Hz, 1 H), 7.03 (d, J=2.37 Hz, 1 H), 7.14 (s, 1 H), 7.18 (m, 5 H), 7.35 (m, 1 H) Example 688
Η NMR (300 MHz, CD3OD) δ ppm 0.76 (t, J=6.78 Hz, 6 H), 0.89 (m, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 2.01 ( , 2 H), 2.50 (m, 2 H), 2.67 (d, J=1.70 Hz, 1 H), 2.69 (s, 3 H), 2.78 (m, 1 H), 2.85 (d, J=3.73 Hz, 3 H), 2.90 (m, 1 H), 2.98 (m, 2 H), 3.04 (m, 1 H), 3.11 (m, 1 H), 3.20 (m, 2 H), 3.37 (m, 1 H), 3.71 (m, 1 H), 3.77 (m, 1 H), 4.13 (m, 1 H), 4.42 (s, 2 H), 6.75 (d, J=8.14 Hz, 1 H), 6.85 (d, J=2.37 Hz, 1 H), 6.98 (dd, J=8.14, 2.37 Hz, 1 H), 7.07 (m, 3 H), 7.15 (m, 2 H), 7.19 (s, I H) Example 689
Η NMR (300 MHz, CD3OD) δ ppm 0.76 (t, J=6.27 Hz, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.78 Hz, 3 H), 2.02 (m, 2 H), 2.50 (m, 2 H), 2.69 (s, 3 H), 2.76 (s, 6 H), 2.91 (dd,
J=13.73, 6.95 Hz, 1 H), 2.99 (m, 1 H), 3.04 (m, 1 H), 3.11 (m, 1 H), 3.17 (m, 1 H), 3.23 (m, 2 H), 3.34 (d, J=2.37 Hz, 1 H), 3.37 (m, 1 H), 3.71 (d, J=11.19 Hz, 1 H), 3.77 (m, 1 H), 4.13 (m, 1 H), 4.42 (s, 2 H), 6.90 (m, 1 H), 7.08 (m, 3 H), 7.15 (m, 2 H), 7.19 (s, 1 H), 7.37 (m, 2
H) Example 690
Η NMR (300 MHz, CD3OD) δ ppm 0.77 (dd, J=6.61, 2.20 Hz, 6 H), 0.91 (dd, J=9.49, 6.44 Hz, 6 H), 1.16 (t, J=7.29 Hz, 3 H), 2.03 (m, 1 H), 2.50 (m, 1 H), 2.70 (s, 3 H), 2.94 (m, 1 H), 3.12 (m, 2 H), 3.28 (m, 9 H), 3.46 (dd, J=15.09, 3.56 Hz, 1 H), 3.75 (d, J=11.19 Hz, 2 H), 4.09 (s, 1 H), 4.40 (m, 2 H), 6.90 (d, J=8.48 Hz, 1 H), 7.07 (m, 3 H), 7.16 (m, 2 H), 7.19 (d, J=4.07 Hz, 1 H), 7.30 (dd, J=8.48, 2.37 Hz, 1 H), 7.99 (d, J=9.49 Hz, 1 H), 8.45 (m, 1 H) Example 691
Η NMR (300 MHz, CD3OD) δ ppm 0.77 (dd, J=6.61, 1.53 Hz, 6 H), 0.89 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 2.02 (m, 1 H), 2.51 (m, 1 H), 2.70 (s, 3 H), 2.94 (dd, J=13.90, 7.12 Hz, 2 H), 3.11 (m, 4 H), 3.21 (m, 3 H), 3.46 (dd, J=14.75, 3.22 Hz, 1 H), 3.77 (m, 3 H), 3.79 (m, 3 H), 4.08 (m, 1 H), 4.42 (m, 2 H), 6.94 (d, J=8.48 Hz, 1 H), 7.08 (m, 3 H), 7.15 (m, 2 H), 7.20 (s, 1 H), 7.39 (dd, J=8.48, 2.37 Hz, 1 H), 7.90 (d, J=9.49 Hz, 1 H), 8.34 (s, 1 H) Example 692
Η NMR (300 MHz, CD3OD) δ ppm 0.77 (d, J=6.78 Hz, 6 H), 0.89 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 2.02 (m, 1 H), 2.47 (m, 1 H), 2.50 (m, 2 H), 2.69 (s, 3 H), 2.94 (dd, J=14.07, 6.61 Hz, 2 H), 3.05 (m, 2 H), 3.14 (m, 1 H), 3.20 (m, 1 H), 3.48 (dd, J=15.09, 3.22 Hz, 1 H), 3.75 (m, 2 H), 4.12 (m, 1 H), 4.41 (m, 2 H), 5.27 (s, 2 H), 6.95 (d, J=8.48 Hz, 1 H), 7.07 (m, 3 H), 7.14 (dd, J=5.93, 3.90 Hz, 2 H), 7.17 (s, 1 H), 7.31 (m, 1 H), 7.37 (m, 6 H), 7.44 (m, 1 H), 7.89 (d, J=9.49 Hz, 1 H) Example 693 Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 1.83 (dd, J=8.14, 6.78 Hz, 1 H), 2.14 (m, 1 H), 2.26 (s, 3 H), 2.69 (s, 3 H), 2.72 (m, 2 H), 2.79 (m, 1 H), 2.97 (m, 1 H), 3.03 (m, 1 H), 3.10 (m, 2 H), 3.17 (m, 2 H), 3.26 (m, 2 H), 3.64 (d, J=10.85 Hz, 1 H), 3.75 (m, 1 H), 3.92 (d, J=3.05 Hz, 1 H), 4.17 (m, 3 H), 4.41 (m, 2 H), 6.43 (d, J=8.82 Hz, 1 H), 6.92 (d, J=6.44 Hz, 1 H), 7.14 (dd, J=8.82, 4.07 Hz, 1 H), 7.19 (m, 5 H), 7.60 (d, J=3.39 Hz, 1 H), 7.63 (s, 1 H) Example 694 Η NMR (300 MHz, CDC13) δ ppm 0.80 (d, J=5.09 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 1.92 (d, J=7.46 Hz, J H), 2.21 (d, J=5.09 Hz, 3 H), 2.69 (s, 3 H), 2.74 (d, J=10.51 Hz, 1 H), 2.93 (m, 2 H), 3.25 (m, 6 H), 3.49 (s, 1 H), 3.56 (d, J=l 1.19 Hz, 1 H), 3.70 (d, J=5.43 Hz, 2 H), 4.09 (s, 1 H), 4.43 (m, 2 H), 6.21 (d, J=7.80 Hz, 1 H), 6.85 (s, 1 H), 6.99 (s, 1 H), 7.10 (m, 2 H), 7.19 (m, 3 H), 7.85 (s, 1 H) Example 695
Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.78 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 1.27 (m, 1 H), 1.87 (m, 1 H), 2.15 (m, 1 H), 2.68 (d, J=4.07 Hz, 3 H), 2.72 (s, 3 H), 3.08 (m, 1 H), 3.12 (m, 1 H), 3.19 (m, 2 H), 3.26 (m, 1 H), 3.38 (m, 1 H), 3.40 (m, 1 H), 3.62 (m, 1 H), 3.64 (m, 1 H), 3.78 (m, 2 H), 4.17 (m, 1 H), 4.41 (m, 2 H), 4.47 (s, 1 H), 6.54 (d, J=8.82 Hz, 1 H), 7.08 (m, 1 H), 7.17 (m, 5 H), 7.86 (m,
1 H), 8.24 (d, J=2.37 Hz, 1 H) Example 696
Η NMR (300 MHz, CDC13) δ ppm 0.81 (d, J=3.39 Hz, 3 H), 0.83 (d, J=3.73 Hz, 3 H), 0.91 (d, J=3.73 Hz, 3 H), 0.93 (d, J=4.07 Hz, 3 H), 1.91 (dd, J=13.39, 6.61 Hz, 1 H), 2.18 (m, 1 H), 2.69 (s, 3 H), 2.75 (m, 1 H), 2.83 (d, J=8.48 Hz, 1 H), 2.90 (dd, J=7.46, 2.37 Hz, 2 H), 3.11 (dd, J=14.24, 4.07 Hz, 1 H), 3.18 (m, 2 H), 3.25 (m, 2 H), 3.68 (d, J=10.85 Hz, 1 H), 3.86 (m, 2 H), 4.10 (s, 1 H), 4.41 (s, 2 H), 5.61 (d, J=4.75 Hz, 2 H), 6.51 (d, J=8.82 Hz, 1 H), 6.92 (d, J=6.78 Hz, 1 H), 7.18 (m, 5 H), 7.54 (s, 1 H) Example 697 Η NMR (300 MHz, CDC13) δ ppm 0.73 (d, J=6.44 Hz, 3 H), 0.78 (d, J=6.78 Hz, 3 H), 0.91 (t, J=6.27 Hz, 6 H), 1.86 (t, J=6.78 Hz, 1 H), 2.17 (s, 1 H), 2.29 (s, 3 H), 2.87 (m, 6 H), 3.10 (m, 4 H), 3.49 (s, 1 H), 3.68 (d, J=10.85 Hz, 1 H), 3.90 (m, 1 H), 4.21 (s, 1 H), 4.39 (d, J=15.26 Hz, 1 H), 4.62 (m, 1 H), 6.71 (d, J=8.82 Hz, 1 H), 6.98 (d, J=8.48 Hz, 1 H), 7.16 (m,
2 H), 7.42 (m, 2 H), 7.51 (m, 1 H), 7.55 (s, 1 H), 7.60 (m, 1 H), 7.76 (m, 2 H), 7.84 (d, J=8.14 Hz, 2 H), 8.10 (d, J=1.36 Hz, 1 H), 8.17 (d, J=8.82 Hz, 1 H)
Example 698
Η NMR (300 MHz, CDC13) δ ppm 0.80 (dd, J=8.14, 6.78 Hz, 6 H), 0.89 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.84 (d, J=1.70 Hz, 1 H), 2.16 (m, 1 H), 2.29 (s, 3 H), 2.76 (dd, J=14.07, 10.00 Hz, 1 H), 2.84 (m, 2 H), 2.94 (m, 2 H), 3.04 (m, 1 H), 3.13 (m, 3 H), 3.65 (d, J=10.85 Hz, 1 H), 3.79 (s, 1 H), 4.15 (d, J=15.26 Hz, 1 H), 4.19 (m, 1 H), 4.42 (d, J=15.60 Hz, 1 H), 6.06 (s, 1 H), 6.33 (d, J=9.16 Hz, 1 H), 6.85 (d, J=8.14 Hz, 1 H), 7.19 (m, 5 H), 7.34 (d, J=1.70 Hz, 1 H), 7.50 (dd, J=8.48, 2.37 Hz, 1 H), 7.56 (d, J=1.70 Hz, 1 H), 7.80 (d, J=1.70 Hz, I H) Example 699
Η NMR (300 MHz, CDC13) δ ppm 0.83 (t, J=6.27 Hz, 6 H), 0.90 (t, J=7.12 Hz, 6 H), 1.89 (m, 1 H), 2.21 (m, 1 H), 2.69 (d, J=8.82 Hz, 1 H), 2.82 (m, 1 H), 2.91 (m, 1 H), 3.06 (m, 5 H), 3.17 (m, 1 H), 3.73 (m, 1 H), 3.86 (m, 2 H), 4.31 (m, 1 H), 4.55 (s, 2 H), 4.68 (d, J=15.60 Hz, 1 H), 4.88 (m, 1 H), 6.56 (d, J=8.82 Hz, 1 H), 7.04 (dd, J=8.48, 2.03 Hz, 1 H), 7.15 (m, 5 H), 7.22 (d, J=2.03 Hz, 1 H), 7.28 (s, 1 H), 7.36 (d, J=8.14 Hz, 1 H), 7.59 (m, 1 H), 7.75 (m, 1 H), 8.02 (s, 1 H), 8.11 (d, J=8.48 Hz, 1 H), 8.16 (d, J=7.80 Hz, 1 H) Example 700
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.87 (m, 1 H), 2.13 (m, 1 H), 2.69 (s, 3 H), 2.74 (m, 1 H), 2.88 (dd, J=13.56, 7.12 Hz, 2 H), 2.94 (m, 2 H), 3.02 (m, 1 H), 3.07 (t, J=3.73 Hz, 2 H), 3.17 (m, 4 H), 3.61 (d, J=10.85 Hz, 1 H), 3.71 (m, 1 H), 3.90 (t, J=6.27 Hz, 2 H), 4.05 (m, 1 H), 4.40 (m, 2 H), 6.47 (d, J=8.82 Hz, 1 H), 6.92 (d, J=6.44 Hz, 1 H), 7.16 (m, 5 H), 7.38 (d, J=8.48 Hz, 2 H), 7.73 (d, J=8.48 Hz, 2 H) Example 701
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.78 Hz, 3 H), 0.86 (t, J=6.61 Hz, 6 H), 0.92 (d, J=6.44 Hz, 3 H), 1.93 (m, 1 H), 2.24 (s, 3 H), 2.78 (dd, J=13.39, 6.61 Hz, 1 H), 2.86 (m, 1 H), 3.17 (m, 1 H), 3.32 (dd, J=15.09, 3.90 Hz, 1 H), 3.84 (d, J=9.16 Hz, 1 H), 4.00 (dd,
J=7.97, 4.24 Hz, 1 H), 4.06 (m, 1 H), 4.27 (m, 2 H), 4.47 (m, 1 H), 4.81 (d, J=7.12 Hz, 2 H),
6.72 (s, 2 H), 6.88 (m, 1 H), 7.00 (d, J=2.03 Hz, 1 H), 7.03 (d, J=2.03 Hz, 1 H), 7.16 (m, 6 H), 7.28 (d, J=2.03 Hz, 2 H), 7.32 (s, 1 H), 7.34 (d, J=3.39 Hz, 1 H)
Example 702 Η NMR (300 MHz, CDC13) δ ppm 0.77 (m, 3 H), 0.81 (m, 3 H), 0.92 (d, J=3.05 Hz, 6 H), 1.92 (s, 1 H), 2.15 (s, 1 H), 2.73 (s, 3 H), 2.79 (s, 2 H), 3.01 (s, 3 H), 3.18 (m, 3 H), 3.27 (s, 3 H), 3.59 (d, J=10.85 Hz, 1 H), 3.80 (s, 1 H), 4.06 (s, 1 H), 4.43 (d, J=20.35 Hz, 2 H), 6.57 (s, 1 H), 7.01 (s, 1 H), 7.17 (s, 5 H), 7.82 (s, 1 H), 8.03 (d, J=2.03 Hz, 1 H) Example 703 Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.44 Hz, 3 H), 0.83 (t, J=7.29 Hz, 3 H), 0.90 (m, 3 H), 0.92 (d, J=4.75 Hz, 3 H), 0.97 (m, 1 H), 1.30 (m, 2 H), 1.87 (m, 1 H), 1.98 (m, 1 H),
2.73 (m, 1 H), 2.81 (m, 1 H), 2.89 (d, J=7.12 Hz, 2 H), 2.93 (d, J=15.26 Hz, 1 H), 3.10 (m, 2 H), 3.19 (m, 2 H), 3.78 (s, 3 H), 3.87 (d, J=10.17 Hz, 2 H), 4.26 (m, 1 H), 4.49 (d, J=15.26 Hz, 1 H), 4.51 (s, 2 H), 4.77 (d, J=15.26 Hz, 1 H), 6.47 (d, J=8.82 Hz, 1 H), 7.03 (dd, J=8.48, 2.03 Hz, 1 H), 7.12 (m, 1 H), 7.19 (m, 5 H), 7.30 (m,'2 H), 7.35 (m, 2 H), 7.74 (m, 1 H) Example 704 Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.85 (t, J=7.29 Hz, 3 H), 0.93 (m, 6 H), 1.00 (m, 1 H), 1.32 (m, 1 H), 1.69 (s, 2 H), 1.90 (m, 2 H), 1.98 (m, 1 H), 2.77 (m, 1 H), 2.89 (m, 2 H), 3.08 (m, 2 H), 3.16 (m, 1 H), 3.80 (d, J=3.73 Hz, 1 H), 3.85 (dd, J=8.31, 3.90 Hz, 1 H), 3.97 (d, J=9.83 Hz, 1 H), 4.31 (m, 1 H), 4.57 (s, 2 H), 4.66 (d, J=15.60 Hz, 1 H), 4.91 (d, J=15.60 Hz, 1 H), 6.59 (d, J=8.82 Hz, 1 H), 7.05 (m, 1 H), 7.16 (m, 6 H), 7.29 (m, 1 H), 7.36 (d, J=8.48 Hz, 1 H), 7.60 (t, J=7.29 Hz, 1 H), 7.76 (t, J=7.12 Hz, 1 H), 8.11 (d, J=8.14 Hz, 1 H), 8.20 (d, J=8.14 Hz, 1 H), 8.88 (d, J=4.41 Hz, 1 H) Example 705 Η NMR (300 MHz, CD3OD) δ ppm 0.71 (d, J=6.78 Hz, 3 H), 0.84 (d, J=7.46 Hz, 3 H), 0.89 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 0.99 (m, 1 H), 1.29 (m, 1 H), 1.84 (m, 1 H), 2.02 (m, 1 H), 2.49 (m, 2 H), 2.93 (dd, J=13.73, 6.95 Hz, 1 H), 3.03 (m, 2 H), 3.11 (m, 2 H), 3.19 (dd, J=13.73, 3.22 Hz, 1 H), 3.41 (dd, J=14.92, 3.73 Hz, 1 H), 3.76 ( , 1 H), 3.85 (d, J=11.19 Hz, 1 H), 4.12 (m, 2 H), 4.41 (d, J=14.92 Hz, 1 H), 4.57 (m, 1 H), 6.99 (m, 4 H), 7.02 (d, J=2.37 Hz, 1 H), 7.14 (m, 2 H), 7.23 (d, J=1.36 Hz, 1 H), 7.26 (d, J=2.03 Hz, 2 H), 7.36 (d, J=8.14 Hz, 1 H), 7.60 (m, 2 H), 7.92 (d, J=9.49 Hz, 1 H), 8.16 (s, 1 H) Example 706
Η NMR (300 MHz, CD3OD) δ ppm 0.73 (m, 3 H), 0.88 (m, 6 H), 0.94 (d, J=6.44 Hz, 3 H), 1.04 (m, 2 H), 1.41 (s, 1 H), 1.90 (s, 1 H), 2.02 (s, 1 H), 2.93 (m, 2 H), 3.02 (m, 2 H), 3.10 (m, 2 H), 3.17 (m, 2 H), 3.25 (m, 2 H), 3.42 (dd, J=14.92, 3.73 Hz, 1 H), 3.78 (s, 1 H), 3.87 (m, 1 H), 4.18 (m, 1 H), 4.53 (d, J=15.60 Hz, 1 H), 4.79 (d, J=15.94 Hz, 1 H), 7.01 (m, 1 H),
7.11 (m, 4 H), 7.19 (m, 2 H), 7.26 (m, 1 H), 7.36 (d, J=8.14 Hz, 1 H), 7.47 (d, J=8.48 Hz, 1 H), 7.59 (t, J=6.95 Hz, 1 H), 7.77 (m, 1 H), 7.93 (d, J=8.14 Hz, 1 H), 8.03 (d, J=8.48 Hz, 1 H), 8.34 (d, J=8.48 Hz, 1 H)
Example 707 Η NMR (300 MHz, CD3OD) δ ppm 0.91 (m, 15 H), 1.09 (m, 1 H), 1.29 (d, J=2.94 Hz, 2 H), 2.01 (m, 1 H), 2.28 (m, 1 H), 2.45 (dd, J=13.60, 11.77 Hz, 1 H), 2.91 (m, 1 H), 2.98 (m, 1 H), 3.06 (m, 1 H), 3.14 (m, 1 H), 3.23 (m, 2 H), 3.27 (m, 1 H), 3.38 (dd, J=14.71, 3.68 Hz, 1 H), 3.75 (m, 1 H), 4.00 (s, 1 H), 4.05 (m, 1 H), 4.59 (m, 2 H), 6.99 (m, 2 H), 7.11 (m, 3 H), 7.24 (m, 1 H), 7.35 (m, 1 H), 7.57 (d, J=10.66 Hz, 1 H), 7.75 (dd, J=7.91, 5.33 Hz, 1 H), 7.92 (m, 1 H), 8.64 (m, 2 H), 9.25 (s, 1 H) Example 708
Η NMR (300 MHz, CD3OD) δ ppm 0.87 (m, 3 H), 0.90 (d, J=6.62 Hz, 3 H), 0.93 (s, 9 H), 1.98 (m, 1 H), 2.28 (m, 1 H), 2.44 (dd, J=13.79, 11.58 Hz, 1 H), 2.92 (m, 1 H), 2.98 (m, 1 H),
3.12 (m, 1 H), 3.17 (m, 1 H), 3.23 (m, 2 H), 3.29 (m, 3 H), 3.35 (m, 1 H), 3.75 (m, 1 H), 4.01 (s, 1 H), 4.06 (s, 1 H), 4.58 (s, 1 H), 4.81 (s, 2 H), 6.73 (m, 2 H), 6.99 (m, 1 H), 7.11 (m, 3 H),
7.24 (m, 1 H), 7.51 (m, 2 H), 7.61 (s, 1 H), 7.81 (dd, J=8.27, 5.33 Hz, 1 H), 7.95 (d, J=9.56 Hz, 1 H), 8.70 (m, 1 H), 9.27 (s, 1 H) Example 709
Η NMR (300 MHz, CDC13) δ ppm 0.92 (d, J=4.78 Hz, 3 H), 0.94 (d, J=4.78 Hz, 3 H), 0.97 (s, 9 H), 1.89 (m, 1 H), 2.44 (m, 1 H), 2.82 (m, 1 H), 2.87 (m, 1 H), 2.91 (m, 1 H), 2.94 (d, J=2.94 Hz, 1 H), 2.98 (m, 1 H), 3.13 (t, J=5.15 Hz, 2 H), 3.18 (m, 2 H), 3.25 (m, 1 H), 3.49 (s, 2 H), 3.77 (d, J=4.04 Hz, 1 H), 3.84 (m, 1 H), 4.12 (s, 1 H), 4.34 (m, 2 H), 4.53 (m, 1 H), 4.67 (s, 1 H), 4.70 (s, 2 H), 6.40 (d, J=9.19 Hz, 1 H), 7.00 (dd, J=8.09, 2.21 Hz, 1 H), 7.10 (m, 1 H), 7.14 (dd, J=8.27, 3.13 Hz, 1 H), 7.18 (d, J=2.94 Hz, 4 H), 7.20 (s, 1 H), 7.35 (d, J=8.46 Hz, 1 H) Example 710 Η NMR (500 MHz, DMSO-d6) δ ppm 0.63 (d, J=6.71 Hz, 3 H), 0.78 (t, J=7.32 Hz, 3 H), 0.82 (dd, J=6.41, 3.36 Hz, 6 H), 0.90 (m, 1 H), 1.26 (m, 1 H), 1.75 (m, 1 H), 1.96 (m, 1 H), 2.42 (m, 1 H), 2.50 (s, 2 H), 2.61 (q, J=8.54 Hz, 1 H), 2.71 (s, 3 H), 2.84 (dd, J=13.43, 6.71 Hz, 1 H), 2.99 (m, 2 H), 3.09 (m, 1 H), 3.21 (m, 2 H), 3.59 (s, 1 H), 3.87 (t, J=11.60 Hz, 1 H),
3.92 (m, 1 H), 4.43 (m, 2 H), 4.94 (d, J=6.10 Hz, 1 H), 5.80 (s, 2 H), 6.87 (d, J=8.54 Hz, 1 H), 6J99 (t, J=7.02 Hz, 1 H), 7.07 (m, 3 H), 7.22 (s, 1 H), 7.36 (d, J=8.54 Hz, 1 H), 7.43 (s, 1
H), 7.85 (d, J=9.16 Hz, 1 H), 8.03 (s, 1 H)
Example 711
Η NMR (300 MHz, CD3OD) δ ppm 0.71 (d, J=6.44 Hz,.3 H), 0.77 (d, J=6.78 Hz, 3 H), 1.00
(d, J=6.10 Hz, 9 H), 2.03 (m, 1 H), 2.49 (m, 2 H), 2.70 (s, 3 H), 3.06 (m, 2 H), 3.22 (m, 3 H), 3.38 (s, 1 H), 3.47 (m, 2 H), 3.68 (d, J=10.85 Hz, 1 H), 3.87 (m, 1 H), 4.00 (m, 1 H), 4.42 (m,
2 H), 7.10 (m, 5 H), 7.22 (s, 1 H), 7.77 (m, 2 H), 7.87 (m, 3 H), 8.14 (s, 1 H)
Example 712
Η NMR (300 MHz, DMSO-d6) δ ppm 0.69 (m, 6 H), 0.81 (d, J=5.43 Hz, 6 H), 1.95 (m, 2
H), 2.40 (m, 1 H), 2.57 (m, 1 H), 2.63 (s, 3 H), 2.91 (q, J=6.78 Hz, 4 H), 3.02 (d, J=10.17 Hz, 4 H), 3.13 (m, 4 H), 3.25 (s, 1 H), 3.57 (s, 1 H), 3.76 (d, J=10.85 Hz, 1 H), 3.89 (s, 1 H), 4.33
(s, 2 H), 7.08 (m, 4 H), 7.22 (s, 1 H), 7.78 (d, J=3.05 Hz, 2 H), 7.90 (s, 1 H), 7.93 (s, 4 H),
8.85 (s, 1 H)Example 715
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.83 (d, J=6.78 Hz, 3 H), 0.86
(d, J=6.44 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 1.85 (m, 1 H), 2.15 (m, 1 H), 2.69 (s, 3 H), 2.74 (m, 1 H), 2.85 (dd, J=13.56, 7.12 Hz, 1 H), 2.95 (d, J=8.14 Hz, 1 H), 3.02 (m, 1 H), 3.08
(m, 2 H), 3.13 (m, 1 H), 3.21 (m, 1 H), 3.49 (d, J=5.43 Hz, 1 H), 3.63 (d, J=11.19 Hz, 1 H),
3.75 (d, J=9.16 Hz, 2 H), 4.17 (d, J=1.70 Hz, 1 H), 4.41 (m, 2 H), 6.50 (d, J=9.16 Hz, 1 H),
6.93 (s, 1 H), 7.18 (m, 5 H), 7.48 (m, 2 H), 7.73 (m, 2 H) Example 716 Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 1.85 (s, 1 H), 2.15 (m, 1 H), 2.69 (m, 3 H), 2.73 (m, 1 H), 2.84 (dd, J=13.56, 6.78 Hz, 1 H), 2.98 (m, 1 H), 3.09 (m, 2 H), 3.15 (m, 2 H), 3.22 (m, 2 H), 3.64 (d, J=10.85 Hz, 1 H), 3.76 (m, 1 H), 4.17 (s, 1 H), 4.42 (m, 2 H), 6.49 (d, J=8.82 Hz, 1 H), 6.92 (d, J=6.44 Hz, 1 H), 7.18 (m, 6 H), 7.79 (m, 2 H), 7.82 (m, 2 H) Example 717
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.84 (d, J=6.44 Hz, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.87 (d, J=7.46 Hz, 1 H), 2.17 (m, 1 H), 2.69 (s, 3 H), 2.72 (d, J=4.41 Hz, 1 H), 2.79 (m, 1 H), 2.89 (m, 1 H), 2.94 (dd, J=12.38, 7.63 Hz, 1 H), 3.01 (d, J=7.80 Hz, 1 H), 3.08 (m, 1 H), 3.13 (m, 2 H), 3.19 (m, 2 H), 3.24 (m, 1 H), 3.63 (d, J=10.85 Hz, 1 H), 3.77 (s, 1 H), 4.16 (s, 1 H), 4.41 (m, 2 H), 6.56 (d, J=8.48 Hz, 1 H), 6.92 (m, 1 H), 7.19 (m, 5 H), 7.56 (dd, J=8.31, 2.20 Hz, 1 H), 7.75 (m, 1 H) Example 718
Η NMR (300 MHz, CDC13) δ ppm 0.81 (d, J=6.78 Hz, 3 H), 0.85 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.44 Hz, 6 H), 1.94 (m, 1 H), 2.13 (m, 1 H), 2.42 (m, 3 H), 2.64 (m, 1 H), 2.69 (d, J=3.39 Hz, 3 H), 2.89 (m, 2 H), 3.05 (m, 1 H), 3.14 (m, 2 H), 3.20 (m, 1 H), 3.39 (dd, J=15.09, 2.20 Hz, 1 H), 3.50 (d, J=7.80 Hz, 1 H), 3.57 (m, 1 H), 3.62 (s, 3 H), 3.71 (d, J=10.85 Hz, 1 H), 3.93 (m, 1 H), 4.24 (m, 1 H), 4.46 (m, 2 H), 6.35 (d, J=9.49 Hz, 1 H), 6.95 (s, 1 H), 7.16 (m, 5 H), 7.36 (s, 1 H) Example 719
Η NMR (300 MHz, CDC13) δ ppm 0.81 (d, J=6.44 Hz, 3 H), 0.84 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.44 Hz, 6 H), 1.95 (m, 1 H), 2.13 (m, 1 H), 2.60 (m, 1 H), 2.68 (m, 1 H), 2.69 (s, 3 H), 2.92 (dd, J=7.46, 2.03 Hz, 2 H), 3.05 (m, 1 H), 3.12 (m, 2 H), 3.20 (m, 1 H), 3.41 (dd,
J=15.26, 2.37 Hz, 1 H), 3.51 (m, 1 H), 3.77 (s, 3 H), 3.92 (s, 1 H), 4.24 (dd, J=9.66, 6.27 Hz, 1 H), 4.44 (m, 2 H), 5.98 (s, 1 H), 6.41 (d, J=9.83 Hz, 1 H), 6.95 (s, 1 H), 7.12 (m, 5 H), 7.46 (d, J=1.36 Hz, 1 H), 7.51 (d, J=1.02 Hz, 1 H) Example 720 Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.44 Hz, 3 H), 0.86 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.44 Hz, 6 H), 1.88 (s, 1 H), 2.22 (m, 1 H), 2.68 (d, J=5.76 Hz, 3 H), 2.75 (m, 1 H), 2.90 (d, J=8.82 Hz, 1 H), 3.00 (m, 2 H), 3.26 (m, 6 H), 3.60 (d, J=11.19 Hz, 1 H), 3.79 (m, 1 H), 4.15 (s, 1 H), 4.41 (s, 2 H), 6.76 (d, J=7.80 Hz, 1 H), 6.93 (s, 1 H), 7.20 (m, 5 H), 8.30 (d, J=2.37 Hz, 1 H), 8.69 (d, J=2.03 Hz, 1 H) Example 721
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 2 H), 0.85 (t, J=6.27 Hz, 6 H), 0.89 (d, J=6.44 Hz, 3 H), 1.52 (s, 2 H), 1.88 (d, J=6.10 Hz, 1 H), 2.17 (d, J=10.85 Hz, 1 H), 2.69 r (s, 3 H), 2.76 (m, 2 H), 2.97 (t, J=7.29 Hz, 1 H), 3.07 (m, 1 H), 3.20 (m, 4 H), 3.62 (d, J=10.85 Hz, 1 H), 3.73 (d, J=4.07 Hz, 2 H), 4.16 (s, 1 H), 4.41 (d, J=2.03 Hz, 2 H), 6.61 (d, J=8.14 Hz, 1 H), 6.93 (s, 1 H), 7.20 (m, 5 H), 7.79 (m, 2 H), 7.91 (d, J=8.82 Hz, 2 H) Example 722 Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.83 (d, J=6.78 Hz, 3 H), 0.87 (m, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.86 (m, 1 H), 2.16 (m, 1 H), 2.69 (s, 3 H), 2.74 (m, 1 H), 2.87 (m, 1 H), 3.00 (m, 1 H), 3.15 (m, 4 H), 3.25 (m, 1 H), 3.64 (d, J=11.19 Hz, 1 H), 3.77 (m, 2 H), 4.17 (m, 1 H), 4.41 (m, 2 H), 6.51 (d, J=8.82 Hz, 1 H), 6.93 (s, 1 H), 7.17 (m, 6 H), 7.29 (m, 1 H), 7.50 (m, 2 H), 7.59 (m, 1 H) Example 723
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.83 (d, J=6.44 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 1.85 (m, 1 H), 2.16 (m, 1 H), 2.68 (d, J=5.09 Hz, 3 H), 2.74 (m, 1 H), 2.85 (dd, J=13.39, 6.95 Hz, 1 H), 2.97 (m, 1 H), 3.07 (m, 2 H), 3.13 (m, 2 H), 3.23 (m, 2 H), 3.64 (d, J=11.19 Hz, 1 H), 3.76 (m, 2 H), 4.17 (m, 1 H), 4.39 (m, 2 H), 6.53 (d, J=8.48 Hz, 1 H), 6.92 (d, J=6.44 Hz, 1 H), 7.16 (m, 5 H), 7.64 (m, 4 H) Example 724
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.83 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.91 (m, 3 H), 1.86 (m, 1 H), 2.17 (m, 1 H), 2.69 (s, 3 H), 2.76 (m, 1 H), 2.94 (dd, J=14.41, 7.63 Hz, 2 H), 3.13 (m, 2 H), 3.23 (m, 2 H), 3.64 (d, J=11.19 Hz, 1 H),
3.77 (m, 2 H), 4.17 (m, 1 H), 4.41 (m, 2 H), 6.58 (d, J=8.48 Hz, 1 H), 6.93 (m, 1 H), 7.16 (m, 6 H), 7.69 (m, 2 H), 7.88 (dd, J=6.78, 2.37 Hz, 1 H), 7.88 (dd, J=6.78, 2.37 Hz, 1 H) Example 725 Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.85 (dd, J=8.14, 6.78 Hz, 1 H), 2.14 (m, 1 H), 2.69 (s, 3 H), 2.73 (m, 1 H), 2.81 (dd, J=13.56, 6.78 Hz, 1 H), 2.99 (m, 1 H), 3.04 (m, 1 H), 3.11 (m, 1 H), 3.20 (m, 4 H), 3.64 (d, J=10.85 Hz, 1 H), 3.75 (s, 1 H), 3.85 (s, 1 H), 3.93 (s, 3 H), 3.94 (s, 3 H), 4.18 (m, 1 H), 4.41 (m, 2 H), 6.43 (d, J=8.82 Hz, 1 H), 6.92 (d, J=5.76 Hz, 1 H), 6.95 (s, 1 H), 7.15 (m, 5 H), 7.40 (d, J=2.37 Hz, 1 H), 7.43 (d, J=2.37 Hz, 1 H) Example 726
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.78 Hz, 3 H), 0.83 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 1.86 (m, 1 H), 2.17 (m, 1 H), 2.69 (s, 3 H), 2.74 (m, 1 H), 2.80 (d, J=8.82 Hz, 1 H), 2.94 (dd, J=13.22, 7.46 Hz, 2 H), 3.07 (m, 1 H), 3.14 (dd, J=6.44, 3.05 Hz, 2 H), 3.18 (m, 1 H), 3.24 (m, 1 H), 3.63 (d, J=11.19 Hz, 1 H), 3.76 (m, 2 H), 4.17 (m, 1 H), 4.41 (m, 2 H), 6.57 (d, J=8.48 Hz, 1 H), 6.93 (s, 1 H), 7.17 (m, 5 H), 7.59 (m, 2 H), 7.88 (d, J=2.03 Hz, 1 H) Example 727
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 1.86 (m, 1 H), 2.14 (m, 1 H), 2.65 (m, 3 H), 2.69 (m, 3 H), 2.74 (m, 1 H), 2.89 (dd, J=13.56, 7.12 Hz, 1 H), 3.01 (m, 1 H), 3.10 (m, 3 H), 3.19 (m, 2 H), 3.26 (m, 1 H), 3.63 (d, J=10.85 Hz, 1 H), 3.76 (m, 2 H), 4.16 (dd, J=8.82, 5.09 Hz, 1 H), 4.41 (m, 2 H), 6.53 (d, J=8.48 Hz, 1 H), 6.92 (d, J=5.76 Hz, 1 H), 7.17 (m, 5 H),
7.88 (m, 2 H), 8.06 (m, 2 H) Example 728
Η NMR (300 MHz, CDC13) δ ppm 0.80 (d, J=7.46 Hz, 6 H), 0.85 (dd, J=7.12, 4.41 Hz, 6 H), 1.86 (m, 1 H), 2.17 (m, 1 H), 2.68 (d, J=3.73 Hz, 3 H), 2.77 (m, 1 H), 3.02 (dd, J=14.07, 4.58 Hz, 1 H), 3.19 (m, 5 H), 3.43 (m, 2 H), 3.48 (d, J=4.41 Hz, 1 H), 3.61 (d, J=11.19 Hz, 1 H), 3.82 (m, 1 H), 4.16 (m, 1 H), 4.41 (m, 2 H), 6.56 (d, J=8.48 Hz, 1 H), 6.92 (d, J=6.78 Hz, 1 H), 7.15 (m, 5 H), 7.45 (m, 2 H) Example 729 Η NMR (300 MHz, CDC13) δ ppm 0.81 (m, 6 H), 0.86 (m, 6 H), 1.86 (d, J=6.78 Hz, 1 H), 2.18 (m, 1 H), 2.68 (d, J=5.76 Hz, 3 H), 2.80 (m, 1 H), 3.04 (dd, J=14.41, 4.58 Hz, 1 H), 3.18 (m, 4 H), 3.39 (m, 2 H), 3.62 (m, 2 H), 3.84 (d, J=4.07 Hz, 1 H), 4.18 (d, J=8.48 Hz, 1 H), 4.42 (m, 2 H), 6.65 (d, J=8.14 Hz, 1 H), 6.94 (s, 1 H), 7.18 (m, 5 H), 7.65 (m, 1 H), 7.70 (dd, J=5.76, 1.70 Hz, 1 H), 7.74 (m, 1 H), 7.85 (m, 1 H), 8.08 (m, 1 H) Example 730
Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.78 Hz, 3 H), 0.84 (d, J=6.78 Hz, 3 H), 0.86 (s, 3 H), 0.89 (m, 3 H), 1.86 (m, 1 H), 2.18 (m, 1 H), 2.69 (s, 3 H), 2.75 (m, 1 H), 2.86 (m, 1 H), 2.96 (m, 2 H), 3.07 (m, 1 H), 3.20 (m, 4 H), 3.63 (d, J=10.85 Hz, 1 H), 3.76 (m, 2 H), 4.18 (d, J=9.16 Hz, 1 H), 4.41 (m, 2 H), 6.63 (d, J=8.48 Hz, 1 H), 6.92 (d, J=7.12 Hz, 1 H), 7.20 (m, 5 H), 7.63 (m, 1 H), 7.84 (m, 1 H), 8.02 (dd, J=9.49, 1.70 Hz, 1 H), 8.08 (s, 1 H) Example 731 Η NMR (300 MHz, CDC13) δ ppm 0.83 (t, J=6.44 Hz, 6 H), 0.88 (m, 3 H), 0.90 (m, 3 H),
1.89 (m, 1 H), 2.18 (m, 1 H), 2.68 (d, J=5.76 Hz, 3 H), 2.76 (m, 1 H), 3.08 (m, 3 H), 3.16 (dd, J=9.32, 4.58 Hz, 1 H), 3.22 (m, 1 H), 3.29 (m, 2 H), 3.49 (d, J=5.43 Hz, 1 H), 3.64 (d, J=10.85 Hz, 1 H), 3.70 (d, J=3.73 Hz, 1 H), 3.81 (dd, J=7.63, 4.24 Hz, 1 H), 4.19 (m, 1 H), 4.41 (m, 2 H), 6.57 (d, J=8.48 Hz, 1 H), 6.92 (d, J=7.46 Hz, 1 H), 6.93 (s, 1 H), 7.16 (m, 5 H) Example 732
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.78 Hz, 3 H), 1.90 (m, 1 H), 2.15 (m, 1 H), 2.67 (s, 1 H), 2.68 (d, J=5.43 Hz, 3 H), 2.73 (m, 1 H), 2.87 (m, 1 H), 2.98 (m, 1 H), 3.13 (m, 4 H), 3.22 (m, 1 H), 3.64 (d, J=11.19 Hz, 1 H), 3.73 (d, J=3.05 Hz, 1 H), 3.81 (dd, J=8.48, 4.75 Hz, 1 H), 4.18 (d, J=8.82 Hz, 1 H), 4.41 (m, 2 H), 6.49 (d, J=8.48 Hz, 1 H), 6.93 (s, 1 H), 7.11 (m, 1 H), 7.17 (m, 5 H), 7.58 (m, 2 H) Example 733 Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=3.73 Hz, 3 H), 0.83 (m, 6 H), 0.85 (d, J=6.44 Hz, 3 H), 1.81 (d, J=6.44 Hz, 1 H), 2.17 (m, 1 H), 2.68 (d, J=5.76 Hz, 3 H), 2.80 (t, J=8.82 Hz, 1 H), 3.03 (dd, J=14.24, 4.41 Hz, 1 H), 3.19 (m, 5 H), 3.35 (d, J=5.43 Hz, 2 H), 3.54 (d, J=4.41 Hz, 1 H), 3.62 (d, JM11.19 Hz, 1 H), 3.77 (d, J=5.76 Hz, 1 H), 4.15 (s, 1 H), 4.39 (m, 2 H), 6.51 (d, J=8.82 Hz, 1 H), 6.92 (d, J=6.44 Hz, 1 H), 7.17 (m, 5 H), 7.37 (dd, J=8.65, 2.20 Hz, 1 H), 7.51 (d, J=2.03 Hz, 1 H), 8.02 (d, J=8.48 Hz, 1 H) Example 734 Η NMR (300 MHz, CDC13) δ ppm 0.81 (dd, J=6.44, 5.09 Hz, 9 H), 0.86 (d, J=6.78 Hz, 3 H), 1.83 (m, 1 H), 2.15 (m, 1 H), 2.67 (m, 3 H), 2.79 (q, J=8.59 Hz, 1 H), 3.02 (dd, J=14.24, 4.41 Hz, 1 H), 3.18 (m, 5 H), 3.35 (d, J=5.76 Hz, 2 H), 3.56 (d, J=4.41 Hz, 1 H), 3.61 (m, 1 H), 3.78 (m, 1 H), 4.13 (m, 1 H), 4.41 (m, 2 H), 6.51 (d, J=8.82 Hz, 1 H), 6.92 (d, J=6.44 Hz, 1 H), 7.17 (m, 5 H), 7.34 (t, J=7.97 Hz, 1 H), 7.66 (dd, J=8.14, 1.70 Hz, 1 H), 8.03 (dd, J=7.97, 1.53 Hz, I H) Example 735
Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.44 Hz, 3 H), 0.83 (d, J=6.78 Hz, 3 H), 0.88 (m, 3 H), 0.90 (d, J=6.78 Hz, 3 H), 1.86 (s, 1 H), 2.17 (m, 1 H), 2.39 (d, J=3.73 Hz, 3 H), 2.65 (s, 3 H), 2.70 (m, 3 H), 2.75 (m, 1 H), 2.97 (dd, J=14.24, 7.46 Hz, 1 H), 3.04 (d, J=5.76 Hz, 1 H), 3.10 (m, 1 H), 3.20 (m, 5 H), 3.61 (d, J=10.85 Hz, 1 H), 3.68 (d, J=4.07 Hz, 1 H), 3.77 (s, 1 H), 4.14 (s, 1 H), 4.41 (m, 2 H), 6.56 (d, J=8.82 Hz, 1 H), 7.18 (m, 6 H) Example 736
Η NMR (300 MHz, CDC13) δ ppm 0.81 (m, 9 H), 0.88 (d, J=6.44 Hz, 3 H), 1.79 (m, 1 H), 2.14 (m, 1 H), 2.41 (m, 3 H), 2.68 (d, J=6.44 Hz, 3 H), 2.69 (m, 1 H), 2.90 (m, 1 H), 3.09 (m, 3 H), 3.19 (m, 2 H), 3.45 (m, 1 H), 3.45 (m, 1 H), 3.65 (d, J=10.85 Hz, 1 H), 3.71 (m, 1 H), 3.82 (d, J=3.05 Hz, 1 H), 3.90 (s, 3 H), 4.15 (m, 1 H), 4.41 (m, 2 H), 6.31 (d, J=9.16 Hz, 1 H), 6.78 (s, 1 H), 6.85 (d, J=8.14 Hz, 1 H), 6.93 (s, 1 H), 7.13 (m, 5 H), 7.79 (d, J=8.14 Hz, 1
H)
Example 737 Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.44 Hz, 3 H), 0.83 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.86 (m, 1 H), 2.16 (m, 1 H), 2.28 (d, J=2.71 Hz, 3 H), 2.69 (s, 3 H), 2.74 (m, 2 H), 2.86 (m, 1 H), 2.98 (m, 1 H), 3.15 (m, 3 H), 3.64 (d, J=10.85 Hz, 1 H), 3.76 (m, 1 H), 3.82 (m, 1 H), 4.16 (m, 1 H), 4.41 (m, 2 H), 6.52 (d, J=8.82 Hz, 1 H), 6.92 (d, J=6.78 Hz, 1 H), 7.16 (m, 6 H), 7.67 (dd, J=8.82, 2.03 Hz, 1 H), 7.79 (m, 1 H), 7.83 (d, J=2.03 Hz, 1 H), 8.61 (d, J=8.82 Hz, 1 H) Example 738
Η NMR (300 MHz, CDC13) δ ppm 0.44 (s, 2 H), 0.70 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.78 Hz, 3 H), 0.99 (d, J=6.44 Hz, 3 H), 1.90 (d, J=15.60 Hz, 2 H), 2.37 (d, J=36.28 Hz, 4 H), 2.64 (s, 3 H), 2.84 (m, 4 H), 3.09 (m, 6 H), 3.68 (s, 1 H), 4.17 (s, 2 H), 4.45 (d, J=31.87 Hz, 2 H), 6.61 (s, 1 H), 6.96 (m, 6 H), 7.67 (s, 1 H), 8.39 (s, 1 H) Example 739 Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 2 H), 0.82 (d, J=6.44 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.92 (m, 3 H), 1.89 (d, J=6.44 Hz, 1 H), 2.16 (d, J=6.78 Hz, 1 H), 2.68 (s, 1 H), 2.69 (d, J=3.73 Hz, 3 H), 2.74 (m, 1 H), 2.82 (d, J=8.82 Hz, 1 H), 2.87 (s, 1 H), 2.94 (dd, J=10.68, 7.63 Hz, 1 H), 3.05 (m, 1 H), 3.10 (m, 1 H), 3.15 (d, J=6.44 Hz, 1 H), 3.22 (m, 1 H), 3.60 (m, 1 H), 3.75 (s, 1 H), 3.87 (d, J=3.05 Hz, 1 H), 4.08 (d, J=4.75 Hz, 1 H), 4.41 (s, 2 H), 6.49 (d, J=8.48 Hz, 1 H), 6.95 (s, 1 H), 7.08 (d, J=8.48 Hz, 1 H), 7.18 (m, 5 H), 7.47 (d, J=1.36 Hz, 1 H), 7.51 (m, 1 H), 7.55 (d, J=2.03 Hz, 1 H) Example 740 Η NMR (300 MHz, CDC13) δ ppm 0.74 (dd, J=6.61, 3.22 Hz, 6 H), 0.81 (dd, J=6.61, 2.54 Hz, 6 H), 1.85 (m, 1 H), 2.14 (m, 1 H), 2.67 (m, 3 H), 2.76 (m, 1 H), 3.03 (m, 1 H), 3.16 (m, 5 H), 3.33 (m, 2 H), 3.60 (d, J=11.19 Hz, 1 H), 3.70 (d, J=4.07 Hz, 1 H), 3.79 (m, 1 H), 4.15 (m, 1 H), 4.40 (d, J=3.73 Hz, 2 H), 6.51 (d, J=8.82 Hz, 1 H), 6.91 (m, 1 H), 7.15 (m, 5 H), 7.70 (m, 1 H), 8.19 (d, J=8.48 Hz, 1 H), 8.36 (m, 1 H), 8.44 (d, J=6.10 Hz, 1 H), 8.70 (d, J=6.10 Hz, l H), 9.34 (s, 1 H) Example 741
Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.86 (dd, J=8.14, 6.78 Hz, 1 H), 2.14 (m, 1 H), 2.69 (s, 3 H), 2.70 (m, 1 H), 2.83 (dd, J=13.39, 6.61 Hz, 1 H), 3.03 (m, 1 H), 3.14 (m, 3 H), 3.26 (m, 2 H), 3.62 (d, J=11.19 Hz, 1 H), 3.75 (m, 1 H), 3.84 (d, J=3.39 Hz, 1 H), 3.90 (s, 3 H), 3.91 (s, 6 H), 4.17 (m, 1 H), 4.36 (d, J=15.60 Hz, 1 H), 4.44 (d, J=15.60 Hz, 1 H), 6.45 (d, J=8.82 Hz, 1 H), 6.92 (s, 1 H), 7.03 (s, 2 H), 7.17 (m, 5 H) Example 742
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.84 (d, J=8.14 Hz, 1 H), 2.15 (m, 1 H), 2.44 (d, J=4.41 Hz, 3 H), 2.49 (d, J=10.51 Hz, 1 H), 2.68 (d, J=7.12 Hz, 3 H), 2.69 (m, 2 H), 2.76 (m, 1 H), 2.85 (dd, J=13.56, 6.78 Hz, 1 H), 3.00 (m, 1 H), 3.11 (m, 3 H), 3.21 (m, 2 H), 3.64 (d, J=11.19 Hz, 1 H), 3.78 (m, 1 H), 4.16 (m, 1 H), 4.41 (m, 1 H), 6.48 (d, J=8.82 Hz, 1 H), 6.92 (d, J=9.16 Hz, 1 H), 7.17 (m, 5 H), 7.36 (d, J=7.80 Hz, 1 H), 7.56 (dd, J=7.97, 1,87 Hz, 1 H), 7.77 (d, J=2.03 Hz, 1 H) Example 743
Η NMR (300 MHz, CDC13) δ ppm 0.80 (d, J=6.78 Hz, 6 H), 0.84 (dd, J=6.61, 1.53 Hz, 6 H), 1.83 (m, 1 H), 2.18 (m, 1 H), 2.68 (d, J=3.73 Hz, 3 H), 2.83 (q, J=8.36 Hz, 1 H), 3.00 (dd, J=14.41, 4.58 Hz, 1 H), 3.19 (m, 6 H), 3.41 (m, 2 H), 3.60 (m, 2 H), 3.81 (dd, J=6.95, 4.92 Hz, 1 H), 4.15 (m, 1 H), 4.38 (d, J=16.28 Hz, 2 H), 6.58 (d, J=8.14 Hz, 1 H), 6.93 (s, 1 H), 7.17 (m, 6 H), 7.62 (m, 1 H), 7.72 (m, 1 H) Example 744 Η NMR (300 MHz, CDC13) δ ppm 0.80 (m, 6 H), 0.83 (d, J= .41 Hz, 3 H), 0.85 (d, J=3.73 Hz, 3 H), 1.85 (m, 1 H), 2.17 (m, 1 H), 2.69 (m, 3 H), 2.83 (m, 1 H), 3.02 (dd, J=14.41, 4.58 Hz, 1 H), 3.19 (m, 4 H), 3.38 (d, J=5.76 Hz, 2 H), 3.55 (d, J=4.41 Hz, 1 H), 3.61 (d, J=10.85 Hz, 1 H), 3.79 (d, J=5.09 Hz, 1 H), 4.15 (s, 1 H), 4.41 (s, 2 H), 6.55 (d, J=8.48 Hz, 1 H), 6.93 (s, 1 H), 7.16 (m, 5 H), 7.23 (d, J=6.10 Hz, 1 H), 7.64 (d, J=8.48 Hz, 1 H), 7.75 (s, 1 H), 8.22 (d, J=7.80 Hz, 1 H) Example 745
Η NMR (300 MHz, CDC13) δ ppm 0.79 (dd, J=9.32, 6.61 Hz, 6 H), 0.89 (m, 6 H), 1.92 (m, 2 H), 2.14 (m, 2 H), 2.70 (m, 3 H), 2.78 (m, 2 H), 3.05 (m, 4 H), 3.21 (m, 3 H), 3.78 (d, J=10.85 Hz, 1 H), 3.89 (d, J=5.43 Hz, 1 H), 4.29 (s, 1 H), 4.44 (m, 2 H), 6.96 (m, 1 H), 7.13 (m, 5 H), 7.91 (m, 2 H), 8.14 (d, J=8.82 Hz, 2 H) Example 746
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.78 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.85 (m, 1 H), 2.15 (m, 1 H), 2.68 (d, J=6.78 Hz, 3 H), 2.72 (m, 1 H), 2.83 (m, 1 H), 2.97 (d, J=8.14 Hz, 1 H), 3.02 (dd, J=5.59, 2.54 Hz, 1 H), 3.08 (dd, J=10.51, 3.73 Hz, 1 H), 3.14 (s, 1 H), 3.17 (m, 1 H), 3.24 (m, 1 H), 3.64 (d, J=10.85 Hz, 1 H), 3.76 (m, 1 H), 3.83 (d, J=3.39 Hz, 1 H), 4.17 (m, 1 H), 4.41 (m, 2 H), 6.45 (d, J=8.82 Hz, 1 H), 6.92 (d, J=6.44 Hz, 1 H), 7.14 (m, 1 H), 7.20 (m, 5 H), 7.53 (m, 2 H), 7.58 (m, 1 H), 7.78 (t, J=1.87 Hz, 1 H), 7.81 (m, 1 H) Example 747
Η NMR (300 MHz, CDC13) δ ppm 0.80 (m, 6 H), 0.85 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 1.77 (m, 1 H), 2.16 (m, 1 H), 2.68 (d, J=4.41 Hz, 3 H), 2.75 (m, 1 H), 2.96 (dd, J=14.24, 6.78 Hz, 1 H), 3.11 (m, 4 H), 3.24 (m, 1 H), 3.46 (m, 1 H), 3.65 (d, J=11.19 Hz, 1 H), 3.71 (m, 2 H), 3.90 (d, J=3.73 Hz, 3 H), 4.08 (m, 1 H), 4.15 (m, 1 H), 4.41 (m, 2 H), 6.41 (d, J=8.82 Hz, 1 H), 6.87 (m, 1 H), 6.92 (d, J=6.78 Hz, 1 H), 7.16 (m, 5 H), 7.61 (m, 1 H), 8.05 (m, 1 H) Example 748
Η NMR (300 MHz, CDC13) δ ppm 0.81 (d, J=6.78 Hz, 3 H), 0.86 (m, 6 H), 0.90 (m, 3 H), 1.91 (m, 1 H), 2.16 (m, 1 H), 2.67 (s, 3 H), 2.77 (dd, J=14.24, 10.17 Hz, 1 H), 2.87 (dd, J=13.73, 7.29 Hz, 1 H), 2.96 (m, 2 H), 3.24 (m, 4 H), 3.33 (m, 2 H), 3.82 (d, J=10.85 Hz, 1 H), 3.95 (dd, J=7.97, 4.24 Hz, 1 H), 4.43 (t, J=4.58 Hz, 1 H), 4.48 (m, 2 H), 6.92 (s, 1 H), 7.09 (m, 3 H), 7.16 (m, 4 H), 7.32 (m, 1 H), 7.71 (dd, J=8.14, 1.70 Hz, 1 H), 7.97 (d, J=1.70 Hz, I H) Example 749 Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.78 Hz, 3 H), 1.85 (m, 1 H), 2.14 (m, 1 H), 2.68 (d, J=5.76 Hz, 3 H), 2.73 (m, 1 H), 2.83 (dd, J=13.39, 6.95 Hz, 1 H), 2.99 (m, 1 H), 3.08 (m, 1 H), 3.15 (d, J=8.14 Hz, 2 H), 3.21 (m, 2 H), 3.64 (d, J=10.85 Hz, 1 H), 3.77 (m, 1 H), 3.83 (d, J=3.39 Hz, 1 H), 4.18 (m, 1 H), 4.41 (m, 2 H), 5.43 (m, 1 H), 5.88 (d, J=17.63 Hz, 1 H), 6.45 (d, J=8.82 Hz, 1 H), 6.74 (dd, J=17.63, 10.85 Hz, 1 H), 6.93 (s, 1 H), 7.17 (m, 6 H), 7.51 (m, 2 H), 7.76 (m, 2 H) Example 750
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.83 (dd, J=8.48, 6.78 Hz, 1 H), 2.14 (m, 1 H), 2.69 (s, 3 H), 2.72 (m, 1 H), 2.78 (m, 1 H), 2.95 (d, J=8.48 Hz, 1 H), 3.00 (m, 1 H), 3.14 (m, 4 H), 3.27 (m, 2 H), 3.65 (d, J=10.85 Hz, 1 H), 3.76 (m, 1 H), 3.93 (d, J=2.71 Hz, 1 H), 4.18 (d, J=9.49 Hz, 1 H), 4.41 (m, 2 H), 4.68 (t, J=8.82 Hz, 2 H), 6.41 (d, J=9.49 Hz, 1 H), 6.84 (d, J=8.48 Hz, 1 H), 6.93 (s, 1 H), 7.17 (m, 5 H), 7.56 (d, J=2.37 Hz, 1 H), 7.59 (d, J=2.03 Hz, 1 H), 7.61 (s, 1 H) Example 751 Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.51 (d, J=6.44 Hz, 3 H), 1.89 (m, 1 H), 2.15 (m, 1 H), 2.69 (m, 3 H), 2.74 (m, 1 H), 2.86 (m, 1 H), 3.01 (m, 1 H), 3.10 (m, 3 H), 3.18 (m, 1 H), 3.25 (m, 1 H), 3.59 (dd, J=10.85, 2.37 Hz, 1 H), 3.75 (d, J=9.16 Hz, 2 H), 4.09 (dd, J=8.99, 4.24 Hz, 1 H), 4.35 (m, 3 H), 4.97 (q, J=6.67 Hz, 1 H), 6.41 (t, J=8.99 Hz, 1 H), 6.92 (s, 1 H), 7.15 (m, 5 H), 7.53 (d, J=8.48 Hz, 2 H), 7.76 (d, J=8.48 Hz, 2 H) Example 752
Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.15 (m, 1 H), 2.69 (s, 3 H), 2.71 (m, 2 H), 2.80 (m, 1 H), 2.99 (m, 3 H), 3.16 (m, 5 H), 3.65 (d, J=10.85 Hz, 1 H), 3.75 (m, 1 H), 3.87 (s, 1 H), 4.16 (d, J=14.92 Hz, 1 H), 4.41 (m, 2 H), 6.08 (s, 2 H), 6.46 (d, J=8.82 Hz, 1 H), 6.90 (m, 2 H), 7.17 (m, 5 H), 7.35 (dd, J=8.31, 1.86 Hz, 1 H) Example 753
Η NMR (300 MHz, CDC13) δ ppm 0.86 (m, 12 H), 1.85 (s, 1 H), 2.13 (s, 1 H), 2.69 (s, 3 H), 2.73 (m, 3 H), 3.08 (m, 7 H), 3.64 (m, 1 H), 3.78 (d, J=14.58 Hz, 1 H), 4.17 (s, 1 H), 4.38 (m, 2 H), 6.44 (s, 1 H), 6.88 (d, J=8.14 Hz, 1 H), 6.93 (s, 1 H), 7.14 (m, 3 H), 7.24 (s, 1 H), 7.28 (d, J=2.03 Hz, 1 H), 7.35 (m, 1 H), 7.43 (d, J=7.80 Hz, 1 H), 7.71 (s, 1 H), 7.78 (d, J=2.03 Hz, I H) Example 754
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.83 (d, J=6.78 Hz, 3 H), 0.88 (dd, J=7.97, 6.61 Hz, 6 H), 1.87 (m, 1 H), 2.16 (m, 1 H), 2.69 (d, J=3.73 Hz, 3 H), 2.73 (d, J=4.07 Hz, 1 H), 2.81 (m, 1 H), 2.97 (m, 2 H), 3.07 (m, 1 H), 3.18 (m, 3 H), 3.25 (m, 1 H), 3.62 (d, J=10.85 Hz, 1 H), 3.80 (m, 1 H), 4.16 (dd, J=8.99, 4.92 Hz, 1 H), 4.42 (m, 2 H), 6.62 (d, J=8.48 Hz, 1 H), 6.95 (s, 1 H), 7.18 (m, 6 H), 7.46 (dd, J=7.63, 4.58 Hz, 1 H), 8.09 (m, 1 H), 8.80 (dd, J=4.92, 1.53 Hz, 1 H), 9.02 (d, J=1.70 Hz, 1 H) Example 755
Η NMR (300 MHz, CD3OD) δ ppm 0.76 (t, J=6.10 Hz, 6 H), 0.89 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 1.45 (d, J=6.44 Hz, 9 H), 2.02 (m, 1 H), 2.48 (m, 2 H), 2.69 (m, 3 H), 2.94 (m, 2 H), 3.06 (m, 3 H), 3.15 (m, 2 H), 3.20 (m, 4 H), 3.35 (s, 1 H), 3.47 (m, 1 H), 3.75 (m, 2 H), 3.95 (d, J=12.89 Hz, 1 H), 4.04 (s, 1 H), 4.44 (q, J=15.26 Hz, 2 H), 6.98 (d, J=8.48 Hz, 1 H), 7.09 (m, 2 H), 7.18 (m, 3 H), 7.45 (dd, J=8.48, 2.37 Hz, 1 H), 7.94 (d, J=9.83 Hz, 1 H), 8.53 (d, J=2.03 Hz, 1 H) Example 756
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.78 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.50 (d, J=6.44 Hz, 3 H), 1.83 (s, 1 H), 2.14 (m, 1 H), 2.69 (s, 3 H), 2.74 (m, 1 H), 2.78 (m, 1 H), 2.88 (s, 1 H), 2.96 (m, 1 H), 3.00 (m, 1 H), 3.11 (m, 3 H), 3.21 (m, 1 H), 3.35 (m, 1 H), 3.65 (d, J=10.85 Hz, 1 H), 3.74 (s, 1 H), 3.95 (d, J=2.71 Hz, 1 H), 4.16 (s, 1 H), 4.41 (m, 2 H), 5.04 (m, 1 H), 6.39 (d, J=9.16 Hz, 1 H), 6.80 (d, J=8.82 Hz, 1 H), 6.93 (s, 1 H), 7.17 (m, 5 H), 7.56 (m, 2 H) Example 757
Η NMR (300 MHz, CDC13) δ ppm 0.80 (d, J=6.78 Hz, 3 H), 0.83 (dd, J=6.78, 1.70 Hz, 3 H), 0.88 (m, 6 H), 1.53 (s, 2 H), 1.91 (s, 1 H), 2.17 (s, 1 H), 2.69 (s, 3 H), 2.76 (m, 1 H), 3.05 (d, J=7.46 Hz, 2 H), 3.10 (m, 1 H), 3.23 (m, 4 H), 3.36 (d, J=3.05 Hz, 1 H), 3.62 (d, J=l 1.53 Hz, 1 H), 3.72 (s, 1 H), 3.88 (s, 1 H), 4.17 (s, 1 H), 4.39 (m, 2 H), 5.20 (d, J=3.73 Hz, 1 H), 5.30 (s, 1 H), 6.54 (s, 1 H), 6.69 (d, J=3.39 Hz, 1 H), 6.92 (d, J=5.43 Hz, 1 H), 7.03 (d, J=3.73 Hz, 1 H), 7.19 (m, 4 H), 7.37 (m, 3 H), 7.46 (s, 1 H), 8.01 (s, 1 H) Example 758 Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.78 Hz, 3 H), 0.91 (m, 3 H), 1.87 (m, 1 H), 2.14 (m, 1 H), 2.69 (m, 3 H), 2.75 (m, 1 H),
2.90 (m, 1 H), 3.02 (m, 1 H), 3.11 (m, 3 H), 3.22 (m, 3 H), 3.62 (d, J=10.85 Hz, 1 H), 3.77 (m, 1 H), 3.84 (m, 1 H), 3.97 (s, 3 H), 4.13 (m, 1 H), 4.41 (m, 2 H), 6.49 (d, J=9.16 Hz, 1 H), 6.93 (s, 1 H), 7.17 (m, 5 H), 7.61 (m, 1 H), 7.98 (d, J=7.80 Hz, 1 H), 8.25 (d, J=7.80 Hz, 1 H), 8.44 (d, J=l .70 Hz, 1 H) Example 759
Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 2.65 (m, 3 H), 2.69 (s, 3 H), 2.75 (m, 2 H),
2.91 (m, 2 H), 3.01 (d, J=7.80 Hz, 1 H), 3.10 (d, J=19.67 Hz, 2 H), 3.21 (m, 1 H), 3.27 (m, 3 H), 3.62 (d, J=11.19 Hz, 2 H), 3.78 (d, J=5.76 Hz, 1 H), 3.90 (s, 1 H), 4.19 (s, 1 H), 4.43 (m,
2 H), 6.54 (s, 1 H), 6.93 (s, 1 H), 7.19 (m, 4 H), 7.63 (m, 1 H), 7.99 (d, J=7.80 Hz, 1 H), 8.15 (m, 1 H), 8.36 (s, 1 H) Example 760
Η NMR (300 MHz, CDC13) δ ppm 0.80 (d, J=6.78 Hz, 3 H), 0.88 (m, 9 H), 1.88 (m, 4 H),
2.19 (m, 1 H), 2.70 (s, 3 H), 2.75 (m, 1 H), 2.89 (t, J=7.97 Hz, 1 H), 3.01 (m, 2 H), 3.24 (m, 2 H), 3.63 (d, J=10.85 Hz, 1 H), 3.77 (dd, J=7.63, 4.24 Hz, 2 H), 4.16 (m, 1 H), 4.41 (m, 2 H), 6.75 (d, J=8.14 Hz, 1 H), 6.93 (d, J=9.83 Hz, 1 H), 7.18 (m, 5 H), 7.63 (t, J=5.76 Hz, 2 H),
8.20 (d, J=6.44 Hz, 2 H) Example 761
Η NMR (300 MHz, CDC13) δ ppm 0.80 (dd, J=9.83, 6.78 Hz, 6 H), 0.92 (m, 3 H), 0.96 (d, J=6.78 Hz, 3 H), 1.93 (d, J=8.14 Hz, 1 H), 2.19 (dd, J=9.16, 6.78 Hz, 1 H), 2.68 (d, J=9.16 Hz, 3 H), 2.77 (m, 2 H), 2.89 (m, 2 H), 3.11 (m, 3 H), 3.30 (d, J=7.46 Hz, 2 H), 3.39 (m, 1 H), 3.88 (m, 2 H), 4.29 (s, 1 H), 4.43 (s, 2 H), 6.71 (d, J=8.14 Hz, 1 H), 6.96 (s, 1 H), 7.07 (m, 1 H), 7.17 (m, 5 H), 7.31 (s, 1 H), 7.37 (t, J=7.80 Hz, 1 H), 8.95 (s, 1 H) Example 762 Η NMR (300 MHz, CDC13) δ ppm 0.80 (m, 3 H), 0.84 (d, J=3.39 Hz, 3 H), 0.87 (m, 6 H), 1.91 (d, J=7.46 Hz, 1 H), 2.22 (m, 1 H), 2.71 (m, 3 H), 2.73 (m, 1 H), 2.89 (t, J=8.65 Hz, 1 H), 2.99 (m, 3 H), 3.23 (m, 3 H), 3.31 (m, 2 H), 3.62 (d, J=11.19 Hz, 1 H), 3.83 (dd, J=6.95, 4.92 Hz, 1 H), 4.17 (m, 1 H), 4.41 (d, J=5.09 Hz, 2 H), 6.74 (d, J=8.48 Hz, 1 H), 6.93 (m, 2 H), 7.18 (m, 5 H), 7.51 (dd, J=8.82, 2.37 Hz, 1 H), 7.73 (d, J=2.37 Hz, 1 H) Example 763 Η NMR (300 MHz, CDC13) δ ppm 0.77 (m, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.90 (m, 3 H), 0.94 (dd, J=6.44, 2.37 Hz, 3 H), 1.90 (s, 1 H), 2.11 (m, 1 H), 2.69 (d, J=2.03 Hz, 3 H), 2.78 (d, J=14.92 Hz, 1 H), 2.93 (m, 1 H), 3.07 (m, 4 H), 3.19 (m, 2 H), 3.58 (m, 2 H), 3.68 (m, 2 H), 3.83 (m, 1 H), 4.01 (s, 1 H), 4.36 (m, 2 H), 4.89 (m, 1 H), 6.35 (d, J=8.82 Hz, 1 H), 6.52 (d, J=9.16 Hz, 1 H), 6.93 (s, 1 H), 7.17 (m, 5 H), 7.56 (m, 2 H), 7.79 (dd, J=8.48, 2.37 Hz, 2 H)
Example 764
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.84 (dd, J=10.00, 6.61 Hz, 6 H), 0.90 (d, J=6.78 Hz, 3 H), 1.86 (m, 1 H), 2.16 (m, 1 H), 2.69 (s, 3 H), 2.76 (m, 1 H), 2.93 (m, 2 H), 3.16 (m, 4 H), 3.63 (d, J=l 1.19 Hz, 1 H), 3.77 (s, 2 H), 4.12 (q, J=7.12 Hz, 2 H), 4.41 (m, 2 H), 6.55 (d, J=8.14 Hz, 1 H), 6.92 (d, J=6.78 Hz, 1 H), 7.17 (m, 6 H), 7.98 (m, 4 H), 10.09 (d, J=7.46 Hz, 1 H) Example 765
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.78 Hz, 3 H), 1.89 (m, 1 H), 2.14 (m, 1 H), 2.69 (d, J=4.75 Hz, 3 H), 2.74 (dd, J=15.26, 4.75 Hz, 2 H), 2.87 (dd, J=13.56, 6.78 Hz, 1 H), 3.00 (m, 1 H), 3.07 (m, 2 H), 3.14 (m, 2 H), 3.21 (m, 1 H), 3.58 (d, J=10.85 Hz, 1 H), 3.76 (m, 1 H), 4.08 (m, 1 H), 4.36 ( , 2 H), 4.78 (s, 2 H), 6.41 (d, J=8.82 Hz, 1 H), 6.92 (s, 1 H), 7.17 (m, 6 H), 7.52 (d, J=8.48 Hz, 2 H), 7.78 (d, J=8.48 Hz, 2 H) Example 766
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.86 (s, 1 H), 2.14 (m, 1 H), 2.68 (d, J=4.41 Hz, 3 H), 2.75 (m, 2 H), 2.85 (dd, J=13.05, 6.27 Hz, 1 H), 2.98 (m, 1 H), 3.16 (m, 4 H), 3.63 (d, J=10.85 Hz, 1 H), 3.76 (s, 1 H), 3.85 (s, 1 H), 4.12 (dd, J=14.24, 7.12 Hz, 1 H), 4.43 (m, 2 H), 6.50 (s, 1 H), 6.94 (s, 1 H), 7.16 (m, 6 H), 7.58 (m, 1 H), 7.75 (m, 4 H), 8.44 (s, 1 H) - Example 767 Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.91 (dd, J=6.61, 1.87 Hz, 6 H), 1.88 (m, 2 H), 2.20 (m, 1 H), 2.66 (q, J=8.14 Hz, 1 H), 2.81 (m, 1 H), 2.86 (d, J=7.12 Hz, 1 H), 2.93 (d, J=7.80 Hz, 1 H), 2.97 (dd, J=8.14, 2.37 Hz, 1 H), 3.02 (d, J=8.14 Hz, 1 H), 3.09 (m, 1 H), 3.15 (m, 2 H), 3.25 (t, J=7.80 Hz, 2 H), 3.79 (d, J=9.49 Hz, 1 H), 3.85 (m, 1 H), 4.27 (t, J=10.00 Hz, 1 H), 4.43 (s, 2 H), 4.91 (s, 2 H), 6.73 (d, J=8.82 Hz, 1 H), 7.00 (dd, J=8.14, 2.03 Hz, 1 H), 7.07 (s, 1 H), 7.15 (d, J=2.37 Hz, 2 H), 7.21 (m, 5 H), 7.34 (d, J=8.14 Hz, I H) Example 768
Η NMR (300 MHz, CD3OD) δ ppm 0.77 (dd, J=6.44, 5.09 Hz, 6 H), 0.89 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 2.02 (m, 1 H), 2.21 (s, 3 H), 2.51 (m, 2 H), 2.69 (m, 3 H), 2.94 (m, 2 H), 3.05 (m, 3 H), 3.15 (m, 2 H), 3.22 (m, 1 H), 3.25 (m, 1 H), 3.43 (dd, J=14.92, 3.73 Hz, 1 H), 3.75 (m, 2 H), 4.10 (m, 1 H), 4.42 (m, 2 H), 6.97 (d, J=8.48 Hz, 1 H), 7.08 (m, 3 H), 7.16 (m, 2 H), 7.21 (s, 1 H), 7.45 (dd, J=8.48, 2.37 Hz, 1 H), 7.95 (d, J=9.49 Hz, 1 H), 8.38 (d, J=2.37 Hz, 1 H) Example 769 Η NMR (300 MHz, CD3OD) δ ppm 0.76 (m, 6 H), 0.89 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.78 Hz, 3 H), 1.45 (d, J=6.44 Hz, 9 H), 2.02 (m, 1 H), 2.47 (dd, J=13.73, 11.36 Hz, 1 H), 2.70 (s, 3 H), 2.94 (m, 2 H), 3.03 (m, 2 H), 3.11 (m, 2 H), 3.19 (m, 2 H), 3.28 (s, 3 H), 3.46 (d, J=3.73 Hz, 1 H), 3.75 (t, J=10.85 Hz, 2 H), 3.95 (d, J=12.89 Hz, 1 H), 4.03 (s, 1 H), 4.44 (q, J=15.60 Hz, 2 H), 4.80 (s, 2 H), 6.98 (d, J=8.48 Hz, 1 H), 7.10 (m, 3 H), 7.19 (m, 3 H), 7.45 (dd, J=8.48, 2.37 Hz, 1 H), 7.94 (d, J=9.83 Hz, 1 H) Example 770
Η NMR (300 MHz, CD3OD) δ ppm 0.76 (t, J=6.27 Hz, 6 H), 0.89 (d, J=6.78 Hz, 3 H), 0.92 (d, J=6.44 Hz, 3 H), 2.01 (m, 1 H), 2.48 (dd, J=13.90, 11.19 Hz, 2 H), 2.69 (s, 3 H), 2.94 (m, 2 H), 3.08 (m, 3 H), 3.15 (m, 2 H), 3.22 (d, J=6.44 Hz, 2 H), 3.42 (m, 1 H), 3.75 (m, 2 H), 4.06 (d, J=23.39 Hz, 1 H), 4.41 (s, 2 H), 6.99 (m, 1 H), 7.07 (m, 3 H), 7.15 (m, 2 H), 7.19 (s, 1 H), 7.45 (dd, J=8.48, 2.37 Hz, 1 H), 7.95 (d, J=9.49 Hz, 1 H), 8.37 (s, 1 H), 8.66 (d, J=2.03 Hz, 1 H) Example 771
Η NMR (300 MHz, CD3OD) δ ppm 0.73 (d, J=6.78 Hz, 3 H), 0.76 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 2.00 (m, 1 H), 2.49 (m, 2 H), 2.69 (d, J=5.09 Hz, 3 H), 2.93 (dd, J=14.07, 6.95 Hz, 2 H), 3.04 (m, 2 H), 3.10 (s, 1 H), 3.12 (m, 2 H), 3.21 (m, 2 H), 3.34 (s, 1 H), 3.44 (dd, J=15.09, 3.22 Hz, 1 H), 3.74 (m, 1 H), 3.82 (s, 1 H), 4.07 (m, 1 H), 4.42 (m, 2 H), 6.97 (t, J=8.14 Hz, 1 H), 7.07 (m, 3 H), 7.13 (m, 2 H), 7.20 (s, 1 H), 7.25 (m, 2 H), 7.26 (m, 1 H), 7.34 (m, 1 H), 7.40 (m, 2 H), 7.44 (dd, J=8.48, 2.37 Hz, 1 H), 7.96 (m, 1 H), 8.44 (d, J=2.37 Hz, 1 H) Example 772 Η NMR (300 MHz, CD3OD) δ ppm 0.76 (d, J=3.39 Hz, 3 H), 0.78 (m, 3 H), 0.89 (d, J=6.78 Hz, 3 H), 0.92 (m, 3 H), 1.42 (s, 9 H), 2.03 (m, 2 H), 2.49 (m, 2 H), 2.66 (d, J=6.44 Hz, 2 H), 2.70 (s, 3 H), 2.95 (m, 2 H), 3.01 (s, 1 H), 3.10 (m, 3 H), 3.16 (d, J=4.41 Hz, 3 H), 3.43 (t, J=6.61 Hz, 2 H), 3.49 (s, 1 H), 3.74 (m, 2 H), 4.08 (s, 1 H), 4.42 (s, 2 H), 6.98 (d, J=8.48 Hz, 1 H), 7.08 (m, 3 H), 7.15 (m, 2 H), 7.20 (s, 1 H), 7.45 (dd, J=8.48, 2.37 Hz, 1 H), 7.94 (d, J=9.49 Hz, 1 H), 8.41 (s, 1 H) Example 773
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.86 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.86 (d, J=6.78 Hz, 1 H), 2.15 (m, 1 H), 2.67 (s, 1 H), 2.68 (d, J=4.41 Hz, 3 H), 2.73 (m, 2 H), 2.85 (dd, J=13.56, 7.12 Hz, 1 H), 2.99 (m, 1 H), 3.06 (dd, J=15.09, 3.22 Hz, 2 H), 3.14 (m, 3 H), 3.21 (m, 2 H), 3.63 (d, J=10.85 Hz, 1 H), 3.76 (m, 2 H), 4.16 (dd, J=9.32, 4.92 Hz, 1 H), 4.41 (m, 2 H), 6.47 (d, J=9.16 Hz, 1 H), 6.92 (d, J=6.10 Hz, 1 H), 7.16 (m, 5 H), 7.71 (d, J=8.48 Hz, 2 H), 7.78 (m, 2 H), 8.07 (s, 1 H) Example 774 Η NMR (300 MHz, CDC13) δ ppm 0.80 (m, 6 H), 0.86 (m, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.53 (s, 1 H), 1.81 (m, 1 H), 2.13 (m, 1 H), 2.66 (m, 1 H), 2.69 (s, 3 H), 2.75 (m, 1 H), 2.96 (m, 2 H), 3.08 (m, 4 H), 3.17 (m, 2 H), 3.23 (d, J=8.82 Hz, 1 H), 3.65 (m, 1 H), 3.68 (d, J=2.71 Hz, 1 H), 3.74 (m, 1 H), 4.00 (d, J=2.71 Hz, 1 H), 4.17 (m, 2 H), 4.41 (m, 2 H), 6.35 (d, J=9.16 Hz, 1 H), 6.56 (m, 1 H), 6.93 (s, 1 H), 7.17 (m, 4 H), 7.44 (dd, J=3.90, 2.54 Hz, 2
H) Example 775
Η NMR (300 MHz, CDC13) δ ppm 0.82 (d, J=6.44 Hz, 6 H), 0.91 (d, J=2.71 Hz, 3 H), 0.93 (d, J=3.05 Hz, 3 H), 1.90 (dd, J=13.56, 6.78 Hz, 1 H), 2.16 (m, 1 H), 2.46 (s, 3 H), 2.69 (s, 3 H), 2.73 (m, 2 H), 2.96 (dd, J=7.46, 3.39 Hz, 2 H), 3.12 (m, 2 H), 3.21 (dd, J=8.48, 3.39 Hz, 2 H), 3.71 (m, 2 H), 3.85 (d, J=2.71 Hz, 1 H), 4.15 (m, 1 H), 4.41 (s, 2 H), 5.56 (s, 2 H), 6.44 (d, J=8.82 Hz, 1 H), 6.94 (s, 1 H), 7.16 (m, 6 H) Example 776 Η NMR (300 MHz, CD3OD) δ ppm 0.76 (t, J=6.61 Hz, 6 H), 0.90 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.78 Hz, 3 H), 2.03 (s, 2 H), 2.46 (m, 1 H), 2.48 (d, J=3.05 Hz, 1 H), 2.70 (s, 3 H), 2.96 (m, 4 H), 3.10 (m, 3 H), 3.18 (m, 3 H), 3.35 (m, 1 H), 3.51 (m, 1 H), 3.75 (d, J=11.19 Hz, 2 H), 4.05 (s, 1 H), 4.42 (s, 2 H), 4.76 (s, 2 H), 7.00 (d, J=8.48 Hz, 1 H), 7.06 (m, 3 H), 7.14 (m, 2 H), 7.22 (s, 1 H), 7.46 (dd, J=8.48, 2.37 Hz, 1 H), 7.79 (d, J=9.83 Hz, 1 H), 8.52 (d, J=2.03 Hz, 1 H) Example 777
Η NMR (300 MHz, CD3OD) δ ppm 0.77 (dd, J=6.78, 2.71 Hz, 6 H), 0.91 (m, 6 H), 1.45 (s, 9 H), 2.02 (s, 1 H), 2.47 (s, 1 H), 2.70 (s, 3 H), 3.02 (m, 3 H), 3.17 (m, 3 H), 3.19 (d, J=13.90 Hz, 2 H), 3.52 (s, 1 H), 3.75 (d, J=10.85 Hz, 1 H), 3.91 (s, 1 H), 4.08 (s, 1 H), 4.47 (m, 2 H), 4.72 (d, J=6.10 Hz, 2 H), 4.92 (m, 2 H), 7.09 (m, 3 H), 7.17 (m, 2 H), 7.53 (d, J=7.46 Hz, 1 H), 7.66 (s, 1 H), 7.89 (s, 1 H), 8.20 (d, J=1.70 Hz, 1 H), 8.47 (s, 1 H) Example 778 Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.80 (d, J=6.78 Hz, 3 H), 0.92 (m, 6 H), 1.95 (m, 1 H), 2.13 (m, 1 H), 2.56 (dd, J=14.07, 10.68 Hz, 1 H), 2.61 (m, 1 H), 2.69 (d, J=3.73 Hz, 3 H), 3.04 (m, 3 H), 3.14 (m, 2 H), 3.22 (s, 1 H), 3.30 (m, 1 H), 3.45 (d, J=7.12 Hz, 1 H), 3.68 (d, J=10.85 Hz, 1 H), 4.07 (m, 1 H), 4.36 (d, J=15.26 Hz, 2 H), 4.47 (m, 3 H), 4.74 (m, 1 H), 4.85 (m, 1 H), 6.94 (s, 1 H), 6.98 (d, J=9.16 Hz, 1 H), 7.14 (m, 5 H), 7.51 (m, 1 H), 7.69 (m, 1 H), 7.93 (s, 1 H) Example 779
Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.44 Hz, 3 H), 0.84 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.44 Hz, 6 H), 1.94 (s, 1 H), 2.19 (d, J=10.85 Hz, 1 H), 2.73 (s, 3 H), 2.88 (s, 1 H), 3.06 (m, 1 H), 3.13 (dd, J=10.51, 7.46 Hz, 2 H), 3.23 (d, J=12.21 Hz, 1 H), 3.31 (m, 1 H), 3.42 (m, 1 H), 3.62 (d, J=10.85 Hz, 1 H), 3.87 (s, 1 H), 4.12 (q, J=7.12 Hz, 2 H), 4.17 (s, 1 H), 4.43 (s, 2 H), 6.70 (d, J=8.82 Hz, 1 H), 6.98 (s, 1 H), 7.09 (d, J=3.39 Hz, 1 H), 7.19 (m, 5 H), 7.24 (m, 2 H), 9.74 (s, 1 H) Example 780
Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.44 Hz, 3 H), 0.91 (dd, J=6.78, 4.41 Hz, 6 H), 0.96 (d, J=6.44 Hz, 3 H), 1.52 (s, 2 H), 2.08 (m, 2 H), 2.43 (m, 1 H), 2.69 (d, J=3.73 Hz, 3 H), 2.83 (m, 1 H), 3.04 (m, 1 H), 3.11 (m, 1 H), 3.14 (m, 3 H), 3.24 (m, 1 H), 3.30 (m, 1 H), 3.62 (s, 1 H), 3.92 (d, J=l 1.19 Hz, 1 H), 4.06 (m, 1 H), 4.24 (m, 1 H), 4.47 (m, 2 H), 6.57 (d, J=3.73 Hz, 1 H), 6.96 (d, J=3.39 Hz, 1 H), 7.13 (m, 5 H), 8.05 (s, 1 H) Example 781 Η NMR (300 MHz, CDC13) δ ppm 0.82 (d, J=3.73 Hz, 3 H), 0.84 (d, J=3.39 Hz, 3 H), 0.87 (d, J=4.07 Hz, 3 H), 0.89 (d, J=4.07 Hz, 3 H), 1.94 (m, 1 H), 2.17 (m, 1 H), 2.65 (m, 1 H), 2.69 (m, 3 H), 2.76 (m, 1 H), 3.05 (dd, J=7.46, 3.39 Hz, 1 H), 3.12 (m, 1 H), 3.20 (m, 1 H), 3.27 (m, 1 H), 3.48 (d, J=2.71 Hz, 1 H), 3.53 (d, J=4.75 Hz, 1 H), 3.67 (d, J=10.85 Hz, 1 H), 3.85 (s, 1 H), 4.12 (q, J=7.12 Hz, 1 H), 4.20 (s, 1 H), 4.44 (s, 2 H), 6.69 (d, J=8.82 Hz, 1 H), 6.96 (s, 1 H), 7.06 (d, J=3.73 Hz, 2 H), 7.12 (m, 2 H), 7.17 (m, 4 H), 7.44 (s, 1 H) Example 782
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.87 (d, J=6.44 Hz, 3 H), 0.90 (d, J=6.78 Hz, 3 H), 1.87 (m, 1 H), 2.15 (m, 1 H), 2.69 (s, 3 H), 2.74 (m, 2 H), 3.07 (m, 11 H), 3.63 (d, J=10.85 Hz, 1 H), 3.76 (m, J=20.35 Hz, 2 H), 4.12 (m, 1 H), 4.39 (d, J=15.60 Hz, 1 H), 4.46 (d, J=15.94 Hz, 1 H), 4.99 (s, 1 H), 6.54 (d, J=8.14 Hz, 1 H), 6.94 (s, 1 H), 7.17 (m, 5 H), 7.77 (d, J=8.82 Hz, 2 H), 7.81 (d, J=8.82 Hz, 2 H) Example 783 Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.44 Hz, 3 H), 1.88 (m, 1 H), 2.14 (m, 1 H), 2.68 (m, 3 H), 2.75 (m, 1 H), 2.96 (dd, J=12.89, 7.12 Hz, 2 H), 3.09 (m, 4 H), 3.23 (m, 3 H), 3.61 (d, J=10.85 Hz, 1 H), 3.72 (d, J=8.82 Hz, 2 H), 4.12 (q, J=7.12 Hz, 1 H), 4.41 (m, 2 H), 6.52 (d, J=8.82 Hz, 1 H), 6.93 (s, 1 H), 7.18 (m, 6 H), 7.87 (d, J=8.48 Hz, 2 H), 7.94 (m, 2 H) Example 784
Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.62 Hz, 3 H), 0.85 (dd, J=14.34, 6.99 Hz, 6 H), 0.91 (m, 3 H), 1.00 (m, 1 H), 1.34 (m, 1 H), 1.89 (dd, J=13.97, 6.99 Hz, 2 H), 2.75 (dd, J=14.16, 9.74 Hz, 1 H), 2.85 (m, 1 H), 2.89 (m, 1 H), 2.97 (m, 2 H), 3.01 (m, 1 H), 3.08 (m, 3 H), 3.16 (m, 2 H), 3.75 (d, J=11.03 Hz, 2 H), 4.17 (d, J=6.62 Hz, 1 H), 4.23 (d, J=15.08 Hz, 1 H), 4.45 (m, 1 H), 6.49 (d, J=8.46 Hz, 1 H), 7.19 (m, 5 H), 7.29 (d, J=5.15 Hz, 1 H), 7.59 (m, 1 H), 7.88 (m, 2 H), 7.94 (m, 2 H), 8.51 (s, 1 H), 8.55 (d, J=3.31 Hz, 1 H) Example 785
Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.62 Hz, 3 H), 0.88 (m, 9 H), 1.00 (m, 1 H), 1.36 (m, 1 H), 1.87 (m, 1 H), 1.97 (m, 1 H), 2.78 (m, 1 H), 2.89 (m, 1 H), 2.96 (m, 2 H), 3.04 (m, 3 H), 3.17 (m, 2 H), 3.24 (m, 1 H), 3.77 (m, 3 H), 4.20 (m, 2 H), 4.45 (m, 1 H), 6.58 (d, J=8.46 Hz, 1 H), 7.19 (m, 5 H), 7.59 (m, 1 H), 7.80 (m, 2 H), 7.91 (m, 2 H), 8.51 (d, J=1.84 Hz, 1 H), 8.55 (dd, J=4.78, 1.47 Hz, 1 H) Example 787 Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.78 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.86 (s, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.33 (t, J=7.63 Hz, 3 H), 1.82 (m, 1 H), 2.08 (m, 1 H), 2.65 (dd, J=14.07, 10.68 Hz, 1 H), 2.76 (dd, J=13.22, 6.44 Hz, 1 H), 2.97 (m, 4 H), 3.07 (dd, J=13.90, 4.07 Hz, 1 H), 3.16 (d, J=8.82 Hz, 1 H), 3.22 (d, J=17.97 Hz, 1 H), 3.58 (d, J=17.97 Hz, 1 H), 3.80 (m, 1 H), 3.83 (d, J=3.73 Hz, 1 H), 3.90 (d, J=11.19 Hz, 1 H), 4.16 (s, 2 H), 4.23 (m, 1 H), 4.76 (m, 2 H), 6.16 (d, J=9.49 Hz, 1 H), 6.68 (m, 2 H), 7.00 (s, 1 H), 7.09 (s, 5 H), 7.56 (m, 2 H) Example 788 Η NMR (300 MHz, CDC13) δ ppm 0.80 (t, J=6.10 Hz, 6 H), 0.89 (m, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.33 (m, 3 H), 1.84 (m, 1 H), 2.08 (m, 1 H), 2.67 (dd, J=14.07, 10.68 Hz, 1 H), 2.85 (m, 2 H), 3.06 (t, J=3.39 Hz, 1 H), 3.25 (d, J=17.63 Hz, 1 H), 3.60 (d, J=17.63 Hz, 1 H), 3.64 (s, 1 H), 3.87 (m, 2 H), 3.96 (m, 1 H), 4.24 (m, 1 H), 4.43 (s, 2 H), 4.75 (d, J=6.10 Hz, 2 H), 4.83 (m, 2 H), 6.26 (d, J=9.16 Hz, 1 H), 7.01 (s, 1 H), 7.03 (t, J=2.54 Hz, 1 H), 7.06 (t, J=2.37 Hz, 1 H), 7.13 (m, 5 H), 7.18 (d, J=2.03 Hz, 1 H), 7.37 (d, J=8.48 Hz, 1 H) Example 789
Η NMR (300 MHz, CD3OD) δ ppm 0.78 (dd, J=6.61, 2.88 Hz, 6 H), 0.87 (d, J=6.78 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 2.00 (m, 2 H), 2.45 (m, 1 H), 2.65 (s, 3 H), 2.88 (m, 3 H), 3.03 (m, 1 H), 3.22 (m, 1 H), 3.39 (dd, J=14.58, 3.73 Hz, 1 H), 3.68 (d, J=18.31 Hz, 1 H), 3.77 (m, 1 H), 4.00 (d, J=10.85 Hz, 1 H), 4.15 (m, 2 H), 4.73 (d, J=6.44 Hz, 2 H), 6.90 (m, 2 H), 6.99 (m, 3 H), 7.13 (m, 2 H), 7.22 (m, 1 H), 7.67 (m, 2 H), 8.21 (d, J=9.83 Hz, 1 H) Example 790 Η NMR (300 MHz, CDC13) δ ppm 0.80 (m, 6 H), 0.89 (d, J=6.78 Hz, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.85 (m, 1 H), 2.09 (m, 1 H), 2.65 (s, 3 H), 2.74 (d, J=11.87 Hz, 1 H), 2.87 (m, 3 H), 3.07 (m, 2 H), 3.15 (m, 1 H), 3.23 (m, 1 H), 3.59 (m, 1 H), 3.83 (m, 1 H), 3.92 (m, 2 H), 4.23 (m, 1 H), 4.43 (s, 2 H), 4.73 (d, J=6.78 Hz, 2 H), 4.80 (d, J=6.44 Hz, 1 H), 6.30 (d, J=9.16 Hz, 1 H), 7.01 (s, 1 H), 7.03 (t, J=2.54 Hz, 1 H), 7.06 (m, 1 H), 7.10 (s, 5 H), 7.19 (m, l H), 7.37 (d, J=8.14 Hz, I H) Example 791
Η NMR (300 MHz, CDC13) δ ppm 0.77 (m, 6 H), 0.89 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.44 Hz, 3 H), 1.86 (m, 1 H), 2.65 (m, 2 H), 2.74 (s, 3 H), 2.85 (m, 2 H), 2.95 (m, 2 H), 2.98 (m, 2 H), 3.07 (m, 2 H), 3.15 (m, 1 H), 3.57 (d, J=17.97 Hz, 1 H), 3.83 (m, 1 H), 3.92 (d, J=11.19 Hz, 1 H), 4.15 (m, 1 H), 4.72 (m, 2 H), 6.68 (d, J=9.16 Hz, 1 H), 6.79 (d, J=8.48 Hz, 1 H), 7.04 (m, 7 H), 7.14 (d, J=2.37 Hz, 1 H)
Example 792
Η NMR (300 MHz, CDC13) δ ppm 0.80 (t, J=6.95 Hz, 6 H), 0.89 (d, J=6.78 Hz, 3 H), 0.94 (d, J=6.78 Hz, 3 H), 1.84 (m, 1 H), 2.08 (m, 1 H), 2.68 (dd, J=14.24, 10.85 Hz, 1 H), 2.84 (m, 1 H), 2.98 (m, 1 H), 3.18 (m, 1 H), 3.27 (d, J=17.97 Hz, 1 H), 3.44 (s, 3 H), 3.48 (d, J=6.10 Hz, 1 H), 3.60 (d, J=17.63 Hz, 1 H), 3.84 (m, 2 H), 3.91 (m, 1 H), 4.25 (m, 1 H), 4.67 (s, 2 H), 4.76 (m, 2 H), 6.24 (d, J=9.16 Hz, 1 H), 7.02 (d, J=2.03 Hz, 1 H), 7.05 (d, J=2.37 Hz, 1 H), 7.11 (s, 6 H), 7.18 (m, 2 H), 7.37 (d, J=8.48 Hz, 1 H) Example 793 Η NMR (300 MHz, CD3OD) δ ppm 0.78 (dd, J=6.61, 3.90 Hz, 6 H), 0.87 (d, J=6.44 Hz, 3 H), 0.90 (d, J=6.44 Hz, 3 H), 1.99 (m, 2 H), 2.46 (dd, J=13.56, 11.87 Hz, 1 H), 2.87 (dd, J=13.73, 6.95 Hz, 1 H), 3.00 (m, 2 H), 3.22 (m, 1 H), 3.35 (m, 2 H), 3.42 (m, 3 H), 3.68 (d, J=18.31 Hz, 1 H), 3.78 (m, 1 H), 4.00 (d, J=10.85 Hz, 1 H), 4.13 (m, 1 H), 4.65 (d, J=5.09 Hz, 2 H), 4.77 (d, J=5.76 Hz, 2 H), 6.90 (m, 2 H), 6.99 (q, J=3.50 Hz, 3 H), 7.12 (m, 2 H), 7.41 (s, 1 H), 7.65 (m, 2 H), 8.20 (d, J=9.49 Hz, 1 H) Example 794
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.86 (s, 3 H), 0.94 (d, J=6.78 Hz, 3 H), 1.82 (m, 1 H), 2.06 (m, 1 H), 2.65 (dd, J=14.24, 10.85 Hz, 1 H), 2.76 (dd, J=13.22, 6.44 Hz, 1 H), 2.95 (m, 1 H), 3.08 (dd, J=13.90, 4.07 Hz, 1 H), 3.20 (m, 2 H), 3.46 (s, 3 H), 3.51 (s, 2 H), 3.59 (m, 1 H), 3.82 (m, 1 H), 3.88 (d, J=10.85 Hz, 1 H), 4.21 (m, 2 H), 4.70 (s, 2 H), 4.79 (m, 2 H), 6.34 (d, J=9.49 Hz, 1 H), 6.69 (d, J=8.82 Hz, 2 H), 7.05 (m, 6 H), 7.24 (s, 1 H), 7.56 (d, J=8.48 Hz, 2 H) Example 795
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.94 (d, J=6.78 Hz, 3 H), 1.83 (m, 1 H), 2.06 (m, 1 H), 2.65 (dd, J=14.07, 10.68 Hz, 1 H), 2.80 (m, 1 H), 2.98 (m, 1 H), 3.05 (m, 1 H), 3.18 (m, 2 H), 3.54 (d, J=17.63 Hz, 1 H), 3.59 (s, 1 H), 3.81 (s, 1 H), 3.87 (d, J=11.19 Hz, 1 H), 4.21 (m, 1 H), 4.38 (s, 2 H), 4.62 (m, 2 H), 6.06 (d, J=9.49 Hz, 1 H), 7.03 (m, 6 H), 7.16 (d, J=2.03 Hz, 1 H), 7.33 (m, 5 H), 7.41 (m, 2 H) Example 796
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.78 Hz, 3 H), 0.81 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.94 (d, J=6.78 Hz, 3 H), 1.83 (m, 1 H), 2.06 (m, 1 H), 2.33 (s, 3 H), 2.64 (dd, J=14.24, 10.51 Hz, 1 H), 2.81 (m, 1 H), 2.98 (m, 1 H), 3.05 (m, 2 H), 3.18 (m, 2 H), 3.54 (d, J=17.97 Hz, 1 H), 3.59 (s, 1 H), 3.84 (s, 1 H), 3.88 (d, J=10.85 Hz, 1 H), 4.21 (m, 1 H), 4.38 (s, 2 H), 4.58 (d, J=2.03 Hz, 2 H), 6.06 (d, J=9.49 Hz, 1 H), 7.05 (m, 6 H), 7.16 (d, J=2.37 Hz, 1 H), 7.22 (m, 4 H), 7.37 (d, J=8.48 Hz, 1 H) Example 797 Η NMR (300 MHz, CDC13) δ ppm 0.80 (d, J=6.78 Hz, 3 H), 0.83 (d, J=6.78 Hz, 3 H), 0.89 (d, J=6.78 Hz, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.85 (m, 1 H), 2.12 (m, 1 H), 2.73 (dd, J=14.24, 10.85 Hz, 1 H), 2.83 (dd, J=13.56, 6.78 Hz, 1 H), 2.97 (m, 1 H), 3.07 (m, 2 H), 3.16 (m, 1 H), 3.37 (d, J=17.97 Hz, 1 H), 3.57 (s, 1 H), 3.66 (d, J=17.97 Hz, 1 H), 3.86 (m, 1 H), 3.93 (d, J=10.51 Hz, 1 H), 4.26 (m, 1 H), 4.85 (m, 2 H), 6.17 (d, J=8.82 Hz, 1 H), 7.03 (dd, J=8.48, 2.03 Hz, 1 H), 7.15 (d, J=4.07 Hz, 5 H), 7.35 (t, J=3.90 Hz, 2 H), 7.39 (m, 1 H), 7.56 (m, 2 H), 7.66 (d, J=7.80 Hz, 1 H) Example 798
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.78 Hz, 3 H), 0.83 (d, J=6.44 Hz, 3 H), 0.90 (m, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.83 (m, 1 H), 2.09 (m, 1 H), 2.69 (dd, J=14.07, 10.68 Hz, 1 H), 2.82 (dd, J=13.56, 6.78 Hz, 1 H), 3.02 (m, 4 H), 3.17 (m, 1 H), 3.30 (d, J=17.97 Hz, 1 H), 3.61 (d, J=17.97 Hz, 2 H), 3.84 (s, 1 H), 3.89 (d, J=10.85 Hz, 1 H), 4.26 (m, 1 H), 4.70 (m, 2 H), 6.11 (d, J=9.16 Hz, 1 H), 7.03 (dd, J=8.14, 2.03 Hz, 1 H), 7.11 (m, 5 H), 7.15 (d, J=2.37 Hz, 1 H), 7.37 (d, J=8.48 Hz, 1 H), 7.52 (t, J=7.97 Hz, 1 H), 7.72 (d, J=7.80 Hz, 1 H), 8.15 (d, J=8.14 Hz, 1 H), 8.24 (t, J=1.87 Hz, 1 H) Example 800
Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.78 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.44 Hz, 3 H), 0.95 (d, J=6.44 Hz, 3 H), 1.82 (m, 1 H), 2.07 (m, 1 H), 2.65 (dd,
J=14.24, 10.85 Hz, 1 H), 2.82 (m, 1 H), 2.99 (m, 2 H), 3.06 (m, 1 H), 3.19 (m, 1 H), 3.53 (s, 1 H), 3.60 (d, J=4.41 Hz, 2 H), 3.82 (m, 1 H), 3.87 (d, J=11.19 Hz, 1 H), 4.24 (m, 1 H), 4.37 (d, J=6.78 Hz, 2 H), 4.62 (m, 2 H), 6.06 (d, J=9.49 Hz, 1 H), 7.05 (m, 4 H), 7.09 (d, J=1.70 Hz, 1 H), 7.14 (s, 1 H), 7.17 (d, J=2.37 Hz, 2 H), 7.26 (d, J=9.83 Hz, 2 H), 7.39 (t, J=3.73 Hz, 1 H) Example 801
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.44 Hz, 3 H), 0.83 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.78 Hz, 3 H), 0.95 (d, J=6.44 Hz, 3 H), 1.83 (dd, J=8.31, 6.61 Hz, 1 H), 2.07 (m, 1 H), 2.67 (dd, J=14.24, 10.85 Hz, 1 H), 2.82 (dd, J=13.56, 6.78 Hz, 1 H), 3.01 (m, 3 H), 3.20 (m, 2 H), 3.58 (m, 2 H), 3.82 (m, 1 H), 3.87 (d, J=10.85 Hz, 1 H), 4.23 (d, J=4.75 Hz, 1 H), 4.37 (d, J=6.78 Hz, 2 H), 4.60 (m, 2 H), 6.06 (d, J=9.49 Hz, 1 H), 7.04 (m, 6 H), 7.17 (m, 2 H), 7.37 (d, J=8.14 Hz, 1 H), 7.44 (m, 2 H) Example 802
Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.44 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.05 (m, 2 H), 2.30 (s, 3 H), 2.65 (dd, J=14.24, 10.85 Hz, 1 H), 2.81 (m, 1 H), 3.01 (m, 2 H), 3.17 (m, 2 H), 3.53 (d,
J=17.97 Hz, 1 H), 3.60 (d, J=3.05 Hz, 1 H), 3.81 (m, 1 H), 3.87 (d, J=10.85 Hz, 1 H), 4.12 (q, J=7.12 Hz, 2 H), 4.22 (m, 1 H), 4.37 (d, J=6.78 Hz, 2 H), 4.57 (m, 2 H), 6.07 (d, J=9.49 Hz, 1 H), 7.02 (d, J=2.37 Hz, 1 H), 7.06 (m, 2 H), 7.13 (d, J=7.80 Hz, 2 H), 7.16 (d, J=2.37 Hz, 1 H), 7.30 (d, J=8.14 Hz, 2 H), 7.37 (d, J=8.48 Hz, 1 H) Example 803
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.84 (d, J=6.78 Hz, 3 H), 0.89 (d, J=6.44 Hz, 3 H), 0.94 (d, J=6.78 Hz, 3 H), 1.83 (dd, J=8.14, 6.78 Hz, 1 H), 2.09 (m, 1 H), 2.70 (dd, J=14.24, 10.85 Hz, 1 H), 2.82 (m, 1 H), 3.01 (m, 3 H), 3.16 (m, 1 H), 3.32 (d, J=17.97 Hz, 1 H), 3.61 (m, 1 H), 3.62 (m, 1 H), 3.84 (m, 1 H), 3.89 (d, J=10.85 Hz, 1 H), 4.27 (m, 1 H), 4.37 (d, J=6.78 Hz, 2 H), 4.69 (m, 2 H), 6.12 (d, J=9.16 Hz, 1 H), 7.03 (m, 1 H), 7.10 (m, 5 H), 7.14 (t, J=2.71 Hz, 1 H), 7.37 (d, J=8.14 Hz, 1 H), 7.54 (m, 2 H), 8.19 (m, I H)
Example 804 Η NMR (300 MHz, CDC13) δ ppm 0.81 (d, J=6.44 Hz, 3 H), 0.89 (m, 6 H), 0.92 (d, J=6.78 Hz, 3 H), 1.84 (m, 1 H), 2.17 (m, 1 H), 2.72 (dd, J=14.07, 10.68 Hz, 1 H), 2.83 (dd, J=13.22, 6.78 Hz, 1 H), 2.96 (m, 1 H), 3.08 (m, 1 H), 3.17 (m, 1 H), 3.43 (d, J=17.97 Hz, 1 H), 3.76 (m, 2 H), 3.85 (m, 1 H), 3.96 (d, J=10.85 Hz, 1 H), 4.27 (m, 1 H), 4.40 (s, 1 H), 4.98 (m, 2 H), 6.26 (d, J=9.16 Hz, 1 H), 7.03 (dd, J=8.31, 2.20 Hz, 1 H), 7.17 (m, 7 H), 7.34 (t, J=8.14 Hz, 2 H), 7.48 (m, 1 H), 7.64 (m, 1 H), 7.76 (d, J=7.80 Hz, 1 H), 7.93 (d, J=8.48 Hz, 1 H), 8.12 (d, J=8.48 Hz, 1 H) Example 805 Η NMR (300 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.12 Hz, 3 H), 0.75 (d, J=6.78 Hz, 3 H), 0.81 (t, J=6.10 Hz, 6 H), 1.96 (m, 2 H), 2.38 (dd, J=13.05, 11.70 Hz, 1 H), 2.83 (m, 2 H), 2.94 (dd, J=8.99, 4.24 Hz, 1 H), 3.02 (d, J=18.31 Hz, 2 H), 3.09 (d, J=3.39 Hz, 1 H), 0.00 (none, 1 H), 3.59 (s, 1 H), 3.88 (s, 3 H), 3.94 (d, J=7.12 Hz, 1 H), 4.02 (d, J=10.85 Hz, 1 H), 4.12 (m, 1 H), 4.93 (d, J=17.29 Hz, 3 H), 5.81 (s, 2 H), 6.88 (dd, J=8.48, 2.03 Hz, 1 H), 6.97 (m, 1 H), 7.13 (m, 5 H), 7.25 (m, 1 H), 7.35 (m, 1 H), 7.48 (d, J=8.14 Hz, 1 H), 7.55 (d, J=7.80 Hz, 1 H), 8.23 (d, J=9.83 Hz, 1 H) Example 806
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.83 (m, 1 H), 2.09 (m, 1 H), 2.66 (dd, J=14.07, 10.68 Hz, 1 H), 2.81 (dd, J=13.56, 6.44 Hz, 1 H), 2.97 (m, 1 H), 3.04 (m, 2 H), 3.18 (m, 1 H), 3.23 (m, 1 H), 3.58 (m, 2 H), 3.82 (m, 1 H), 3.89 (d, J=10.85 Hz, 1 H), 4.24 (s, 1 H), 4.36 (d, J=6.78 Hz, 2 H), 4.66 (m, 2 H), 6.07 (d, J=9.16 Hz, 1 H), 7.02 (m, 1 H), 7.05 (m, 6 H), 7.17 (m, 1 H), 7.34 (m, 1 H), 7.41 (m, 2 H), 7.48 (d, J=8.48 Hz, 2 H), 7.55 (m, 3 H) Example 807 Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.78 Hz, 3 H), 0.83 (d, L 6.44 Hz, 3 H), 5.88 (d, J=6.78 Hz, 3 H), 0.94 (d, J=6.78 Hz, 3 H), 1.82 (dd, J=15.09, 6.61 Hz, 1 H), 2.09 (m, 1 H), 2.67 (dd, J=14.24, 10.51 Hz, 1 H), 2.81 (dd, J=13.39, 6.61 Hz, 1 H), 2.98 (m, 1 H), 3.05 (m, 1 H), 3.19 (m, 1 H), 3.29 (d, J=17.97 Hz, 1 H), 3.61 (m, 2 H), 3.84 (m, 1 H), 3.89 (d, J=10.85 Hz, 1 H), 4.24 (m, 1 H), 4.39 (d, J=6.78 Hz, 2 H), 4.70 (m, 2 H), 6.09 (d, J=9.16 Hz, 1 H), 7.03 (m, 1 H), 7.08 (d, J=1.70 Hz, 5 H), 7.17 (d, J=2.03 Hz, 1 H), 7.37 (d, J=8.48 Hz, 1 H), 7.42 (s, 1 H), 7.46 (d, J=7.80 Hz, 2 H), 7.50 (d, J=8.48 Hz, 2 H), 7.58 (m, 1 H), 7.74 (m, 2 H), 7.78 (d, J=8.48 Hz, 1 H) Example 808 Η NMR (300 MHz, DMSO-d6) δ ppm 0.68 (d, J=6.78 Hz, 3 H), 0.72 (d, J=6.78 Hz, 3 H), 0.82 (d, J=6.10 Hz, 6 H), 0.92 (m, 1 H), 1.94 (m, 1 H), 2.32 (m, 1 H), 2.83 (dd, J=13.90, 6.78 Hz, 1 H), 2.92 (m, 2 H), 3.03 (m, 1 H), 3.21 (dd, J=14.07, 2.88 Hz, 1 H), 3.58 (s, 1 H), 3.83 (d, J=17.97 Hz, 1 H), 3.92 (s, 1 H), 4.02 (d, J=10.51 Hz, 1 H), 5.00 (d, J=6.44 Hz, 1 H), 5.06 (m, 2 H), 5.81 (s, 2 H), 6.81 (m, 3 H), 6.87 (m, 1 H), 7.00 (m, 2 H), 7.22 (d, J=2.03 Hz, 1 H), 7.38 (m, 2 H), 7.49 (m, 1 H), 7.61 (m, 2 H), 7.89 (d, J=8.14 Hz, 1 H), 7.97 (m, 1 H), 8.21 (d, J=9.49 Hz, 1 H), 8.38 (d, J=8.48 Hz, 1 H) Example 809 Η NMR (300 MHz, DMSO-d6) δ ppm 0.70 (dd, J=9.16, 6.78 Hz, 6 H), 0.82 (m, 6 H), 1.94 (m, 2 H), 2.37 (m, 1 H), 2.83 (dd, J=13.73, 6.95 Hz, 1 H), 2.93 (m, 2 H), 3.03 (m, 1 H), 3.22 (m, 1 H), 3.58 (s, 1 H), 3.81 (d, J=18.31 Hz, 1 H), 3.96 (s, 1 H), 4.01 (d, J=10.85 Hz, 1 H), 4.77 (d, J=7.46 Hz, 2 H), 5.00 (d, J=6.44 Hz, 1 H), 5.81 (s, 2 H), 6.82 (m, 3 H), 6.87 (dd, J=8.31, 2.20 Hz, 1 H), 7.03 (m, 2 H), 7.22 (d, J=2.03 Hz, 1 H), 7.36 (d, J=8.48 Hz, 1 H), 7.51 (m, 3 H), 7.82 (s, 1 H), 7.89 (m, 2 H), 7.93 (m, 1 H), 8.22 (d, J=9.49 Hz, 1 H) Example 810
Η NMR (300 MHz, CDC13) δ ppm 0.76 (dd, J=6.61, 2.54 Hz, 3 H), 0.82 (dd, J=6.44, 1.70 Hz, 3 H), 0.89 (d, J=6.44 Hz, 3 H), 0.93 (t, J=6.10 Hz, 3 H), 1.62 (d, J=6.44 Hz, 2 H), 1.85 (m, 1 H), 2.07 (m, 1 H), 2.66 (dd, J=14.07, 10.68 Hz, 1 H), 2.81 (m, 1 H), 2.97 (dd, J=5.59, 2.54 Hz, 1 H), 3.00 (m, 3 H), 3.20 (m, 2 H), 3.52 (d, J=4.07 Hz, 1 H), 3.59 (m, 1 H), 3.82 (s, 1 H), 3.87 (d, J=11.19 Hz, 1 H), 4.23 (s, 1 H), 4.37 (d, J=6.44 Hz, 2 H), 4.61 (m, 2 H), 7.04 (m, 6 H), 7.16 (s, 1 H), 7.36 (d, J=2.37 Hz, 3 H), 7.37 (m, 1 H), 7.41 (m, 1 H) Example 811 Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.83 (d, J=6.78 Hz, 3 H), 0.89 (d, J=6.44 Hz, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.86 (m, 1 H), 2.08 (m, 1 H), 2.55 (s, 3 H), 2.69 (dd, J=14.24, 10.85 Hz, 1 H), 2.82 (dd, J=13.39, 6.61 Hz, 1 H), 2.97 (m, 1 H), 3.06 (m, 1 H), 3.17 (m, 1 H), 3.27 (d, J=17.97 Hz, 1 H), 3.59 (m, 2 H), 3.83 (s, 1 H), 3.88 (d, J=10.85 Hz, 1 H), 4.24 (m, 1 H), 4.39 (s, 2 H), 4.63 (m, 2 H), 6.07 (d, J=9.49 Hz, 1 H), 7.03 (dd, J=8.14, 2.03 Hz, 1 H), 7.10 (m, 5 H), 7.14 (m, 1 H), 7.31 (d, J=7.80 Hz, 1 H), 7.37 (m, 1 H), 7.52 (dd, J=7.80, 1.70 Hz, 1 H), 7.99 (d, J=1.70 Hz, 1 H) Example 812
Η NMR (300 MHz, CDC13) δ ppm 0.83 (m, 6 H), 0.89 (d, J=6.78 Hz, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.83 (m, 1 H), 2.12 (m, 1 H), 2.73 (dd, J=14.24, 10.85 Hz, 1 H), 2.82 (m, 1 H), 3.00 (m, 2 H), 3.08 (m, 1 H), 3.18 (m, 1 H), 3.41 (d, J=17.97 Hz, 1 H), 3.60 (s, 1 H), 3.69 (d,
J=17.97 Hz, 1 H), 3.84 (s, 1 H), 3.90 (d, J=10.85 Hz, 1 H), 4.29 (m, 1 H), 4.38 (s, 1 H), 5.04 (m, 2 H), 6.08 (d, J=9.49 Hz, 1 H), 7.03 (dd, J=8.31, 2.20 Hz, 1 H), 7.16 (m, 7 H), 7.37 (d, J=8.14 Hz, 1 H), 7.44 (m, 1 H), 7.57 (m, 1 H), 8.07 (dd, J=8.14, 1.36 Hz, 1 H) Example 813 Η NMR (300 MHz, CDC13) δ ppm 0.80 (d, J=6.44 Hz, 3 H), 0.84 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.78 Hz, 3 H), 0.94 (d, J=6.78 Hz, 3 H), 1.83 (d, J=1.36 Hz, 1 H), 2.10 (m, 1 H), 2.56 (m, 3 H), 2.72 (dd, J=14.41, 10.68 Hz, 1 H), 2.82 (m, 1 H), 2.98 (m, 1 H), 3.06 (m, 2 H), 3.18 (m, 1 H), 3.36 (d, J=18.31 Hz, 1 H), 3.63 (m, 2 H), 3.86 (s, 1 H), 3.88 (d, J=10.85 Hz, 1 H), 4.27 (d, J=5.76 Hz, 1 H), 4.38 (s, 1 H), 4.69 (m, 2 H), 6.09 (d, J=9.49 Hz, 1 H), 7.03 (dd, J=8.31, 2.20 Hz, 1 H), 7.11 (d, J=7.12 Hz, 5 H), 7.15 (d, J=2.03 Hz, 1 H), 7.30 (m, 1 H), 7.37 (d, J=8.48 Hz, 1 H), 7.52 (d, J=7.46 Hz, 1 H), 7.67 (m, 1 H) Example 814 Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.78 Hz, 3 H), 0.83 (d, J=6.44 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.83 (m, 1 H), 2.10 (m, 1 H), 2.67 (dd, J=13.90, 10.85 Hz, 1 H), 2.81 (m, 1 H), 2.98 (m, 2 H), 3.03 (m, 1 H), 3.16 (m, 1 H), 3.26 (d, J=17.97 Hz, 1 H), 3.60 (m, 2 H), 3.82 (m, 1 H), 3.90 (d, J=10.85 Hz, 1 H), 4.25 (m, 1 H), 4.39 (s, 1 H), 4.67 (m, 2 H), 6.11 (d, J=9.49 Hz, 1 H), 7.02 (m, 1 H), 7.08 (m, 5 H), 7.15 (d, J=2.03 Hz, 1 H), 7.24 (s, 1 H), 7.35 (d, J=8.14 Hz, 1 H), 7.55 (d, J=8.48 Hz, 2 H), 8.02 (m, 2
H)
Example 815
Η NMR (300 MHz, CD3OD) δ ppm 0.75 (dd, J=8.48, 6.78 Hz, 6 H), 0.89 (m, 6 H), 1.98 (m, 1 H), 2.46 (m, 1 H), 2.99 (m, 3 H), 3.21 (dd, J=13.90, 3.39 Hz, 1 H), 3.31 (m, 3 H), 3.40 (dd, J=14.92, 3.73 Hz, 1 H), 3.69 (d, J=18.31 Hz, 1 H), 3.78 (m, 1 H), 3.98 (m, 1 H), 4.13 (m, 1 H), 4.67 (m, 2 H), 6.88 (m, 2 H), 6.99 (dd, J=8.31, 2.20 Hz, 1 H), 7.09 (m, 2 H), 7.23 (m, 2 H), 7.35 (d, J=8.14 Hz, 1 H), 7.45 (dd, J=7.46, 4.41 Hz, 1 H), 7.89 (m, 1 H), 8.49 (m, 1 H), 8.62 (d, J=1.70 Hz, 1 H) Example 816
Η NMR (300 MHz, CD3OD) δ ppm 0.79 (m, 6 H), 0.90 (m, 6 H), 2.02 (m, 2 H), 2.49 (dd, J=13.56, 11.87 Hz, 1 H), 2.92 (m, 1 H), 3.03 (m, 2 H), 3.11 (d, J=3.05 Hz, 1 H), 3.22 (m, 1 H), 3.30 (d, J=1.70 Hz, 3 H), 3.41 (dd, J=14.92, 3.73 Hz, 1 H), 3.78 (m, 2 H), 4.00 (d, J=10.85 Hz, 1 H), 4.16 (m, 1 H), 4.55 (s, 1 H), 4.73 (m, 1 H), 6.98 (d, J=2.03 Hz, 1 H), 7.01 (t, J=2.20 Hz, 1 H), 7.07 (m, 3 H), 7.16 (m, 2 H), 7.22 (s, 1 H), 7.25 (d, J=2.03 Hz, 1 H), 7.30 (dd, J=6.78, 5.43 Hz, 1 H), 7.35 (m, 1 H), 7.37 (m, 1 H) Example 817
Η NMR (300 MHz, CD3OD) δ ppm 0.77 (d, J=6.44 Hz, 6 H), 0.88 (m, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 2.01 (m, 2 H), 2.49 (dd, J=13.73, 11.70 Hz, 1 H), 2.86 (s, 2 H), 2.93 (m, 1 H), 2.99 (m, 2 H), 3.05 (d, J=9.49 Hz, 2 H), 3.11 (m, 1 H), 3.22 (dd, J=13.73, 3.56 Hz, 1 H), 3.41 (dd, J=14.75, 3.90 Hz, 1 H), 3.77 (m, 2 H), 4.00 (d, J=10.85 Hz, 1 H), 4.09 (m, 1 H), 4.55 (s, 1 H), 4.72 (d, J=10.17 Hz, 1 H), 6.99 (m, 3 H), 7.01 (d, J=2.37 Hz, 1 H), 7.14 (dd, J=6.10, 3.05 Hz, 2 H), 7.22 (d, J=4.41 Hz, 1 H), 7.25 (d, J=2.03 Hz, 1 H), 7.35 (d, J=8.14 Hz, 1 H), 7.40 (d, J=6.10 Hz, 2 H) Example 818
Η NMR (300 MHz, CDC13) δ ppm 0.85 (d, J=6.78 Hz, 6 H), 0.89 (d, J=6.44 Hz, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.84 (m, 1 H), 2.14 (m, 1 H), 2.74 (dd, J=14.07, 11.02 Hz, 1 H), 2.83 (m, 1 H), 2.98 (m, 1 H), 3.06 (dd, J=10.85, 3.73 Hz, 1 H), 3.15 (m, 1 H), 3.28 (d, J=17.97 Hz, 1 H), 3.66 (m, 2 H), 3.85 (m, 1 H), 3.94 (d, J=10.85 Hz, 1 H), 3.98 (s, 3 H), 4.27 (m, 1 H), 4.40 (s, 2 H), 4.70 (m, 2 H), 6.10 (d, J=9.16 Hz, 1 H), 6.92 (d, J=9.16 Hz, 1 H), 7.02 (m, 1 H), 7.13 (m, 1 H), 7.16 (d, J=7.46 Hz, 6 H), 7.36 (d, J=8.48 Hz, 1 H), 7.93 (d, J=2.71 Hz, 1 H), 8.15 (dd, J=8.99, 2.88 Hz, I H) Example 819
Η NMR (300 MHz, CDC13) δ ppm 0.73 (d, J=6.78 Hz, 3 H), 0.79 (d, J=6.44 Hz, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.94 (d, J=6.78 Hz, 3 H), 1.83 (d, J=6.78 Hz, 1 H), 2.04 (m, 1 H), 2.71 (dd, J=14.24, 10.51 Hz, 1 H), 2.80 (m, 1 H), 2.98 (m, 1 H), 3.08 (dd, J=14.41, 4.24 Hz, 1 H), 3.16 (m, 1 H), 3.26 (d, J=17.63 Hz, 1 H), 3.54 (d, J=17.97 Hz, 1 H), 3.62 (d, J=3.05 Hz, 1 H), 3.82 (d, J=10.85 Hz, 2 H), 4.25 (s, 1 H), 4.38 (s, 2 H), 5.02 (m, 2 H), 5.97 (d, J=9.49 Hz, 1 H), 7.03 (dd, J=8.31, 2.20 Hz, 1 H), 7.15 (m, 7 H), 7.35 (m, 2 H), 7.44 (m, 1 H), 7.73 (d, J=8.14 Hz, I H) Example 820 Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 3 H), 0.84 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.78 Hz, 3 H), 0.94 (d, J=6.78 Hz, 3 H), 1.83 (m, 1 H), 2.08 (m, 1 H), 2.58 (s, 3 H), 2.69 (dd, J=14.24, 10.51 Hz, 1 H), 2.82 (dd, J=13.56, 6.78 Hz, 1 H), 2.92 (d, J=21.70 Hz, 1 H), 3.04 (m, 1 H), 3.17 (m, 1 H), 3.31 (d, J=17.97 Hz, 1 H), 3.57 (s, 1 H), 3.62 (m, 1 H), 3.83 (dd, J=8.31, 3.22 Hz, 1 H), 3.89 (d, J=10.51 Hz, 1 H), 4.25 (m, 1 H), 4.38 (d, J=6.78 Hz, 2 H), 4.62 (m, 2 H), 6.11 (d, J=9.49 Hz, 1 H), 7.03 (dd, J=8.48, 2.03 Hz, 1 H), 7.11 (m, 5 H), 7.14 (m, 1 H), 7.34 (m, 2 H), 7.37 (d, J=8.14 Hz, 1 H), 7.93 (d, J=9.16 Hz, 1 H) Example 821
Η NMR (300 MHz, CDC13) δ ppm 0.76 (d, J=6.78 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.94 (d, J=6.78 Hz, 3 H), 1.85 (m, 1 H), 2.06 (m, 1 H), 2.64 (dd, J=14.07, 10.68 Hz, 1 H), 2.81 (m, 1 H), 2.98 (m, 1 H), 3.05 (m, 1 H), 3.18 (m, 2 H), 3.37 (s, 3 H), 3.55 (d, J=17.97 Hz, 1 H), 3.60 (s, 1 H), 3.79 (s, 1 H), 3.87 (d, J=10.85 Hz, 1 H), 4.12 (q, J=7.12 Hz, 1 H), 4.22 (m, 1 H), 4.43 (s, 3 H), 4.62 (m, 2 H), 6.06 (d, J=9.49 Hz, 1 H), 7.04 (m, 7 H), 7.17 (d, J=2.03 Hz, 1 H), 7.32 (m, 1 H), 7.34 (m, 2 H), 7.38 (s, 1 H) Example 822 Η NMR (300 MHz, CDC13) δ ppm 0.80 (dd, J=6.44, 2.03 Hz, 6 H), 0.89 (d, J=6.78 Hz, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.86 (s, 1 H), 2.12 (m, 1 H), 2.30 (s, 3 H), 2.75 (dd, J=14.07, 10.68 Hz, 1 H), 2.95 (m, 1 H), 3.06 (m, 1 H), 3.14 (m, 2 H), 3.49 (m, 1 H), 3.59 (d, J=18.31 Hz, 1 H), 3.64 (s, 1 H), 3.76 (m, 1 H), 3.80 (d, J=9.49 Hz, 1 H), 3.87 (m, 3 H), 3.88 (d, J=4.07 Hz, 1 H), 4.11 (s, 1 H), 4.93 (m, 1 H), 6.11 (d, J=8.48 Hz, 1 H), 6.87 (d, J=8.48 Hz, 1 H), 7.15 (m, 6 H), 7.33 (m, 2 H), 7.45 (dd, J=8.31, 2.20 Hz, 1 H), 7.56 (d, J=2.03 Hz, 1 H), 7.65 (d, J=7.80 Hz, 1 H) Example 823
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.44 Hz, 3 H), 0.95 (d, J=6.44 Hz, 3 H), 1.83 (m, 1 H), 2.07 (m, 1 H), 2.66 (dd, J=14.24, 10.85 Hz, 1 H), 2.81 (dd, J=13.39, 6.61 Hz, 1 H), 2.98 (m, 1 H), 3.06 (m, 1 H), 3.20 (m, 2 H), 3.57 (m, 2 H), 3.83 (m, 1 H), 3.88 (d, J=10.85 Hz, 1 H), 4.24 (m, 1 H), 4.38 (s, 2 H), 4.57 (m, 2 H), 6.05 (d, J=9.49 Hz, 1 H), 7.04 (m, 6 H), 7.16 (d, J=2.03 Hz, 1 H), 7.22 (d, J=7.80 Hz, 1 H), 7.33 (s, 1 H), 7.37 (d, J=8.48 Hz, 1 H), 7.43 (d, J=8.14 Hz, 1 H), 7.57 (s, 1
H)
Example 824
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.44 Hz, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.81 (m, 1 H), 2.07 (m, 1 H), 2.59 (d, J=5.76 Hz, 3 H), 2.66 (m, 1 H), 2.82 (dd, J=13.22, 6.78 Hz, 1 H), 3.01 (m, 2 H), 3.17 (m, 1 H), 3.22 (m, 1 H), 3.58 (d, J=17.97 Hz, 1 H), 3.62 (d, J=3.05 Hz, 1 H), 3.83 (dd, J=8.65, 5.26 Hz, 1 H), 3.89 (d, J=10.85 Hz, 1 H), 4.25 (m, 1 H), 4.40 (d, J=6.78 Hz, 2 H), 4.68 (m, 2 H), 6.13 (d, J=9.49 Hz, 1 H), 7.04 (m, 6 H), 7.16 (d, J=2.37 Hz, 1 H), 7.37 (d, J=8.14 Hz, 1 H), 7.44 (t, J=7.63 Hz, 1 H), 7.61 (m, 1 H), 7.88 (d, J=7.80 Hz, 1 H), 7.99 (s, 1 H) Example 825
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.44 Hz, 3 H), 0.82 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.83 (m, 1 H), 2.07 (m, 1 H), 2.63 (dd, J=14.24, 10.85 Hz, 1 H), 2.81 (m, 1 H), 3.00 (m, 2 H), 3.19 (m, 2 H), 3.58 (m, 2 H), 3.82 (m, 1 H), 3.90 (d, J=10.85 Hz, 1 H), 4.21 (s, 1 H), 4.39 (d, J=6.78 Hz, 2 H), 4.72 (m, 2 H), 6.12 (d, J=9.49 Hz, 1 H), 7.04 (m, 7 H), 7.16 (d, J=2.03 Hz, 1 H), 7.51 (m, 2 H), 7.94 (m, 1 H), 8.10 (s, 1 H), 8.51 (d, J=2.37 Hz, 1 H), 8.62 (m, 1 H), 9.02 (d, J=1.36 Hz, 1 H) Example 826 Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.94 (d, J=6.78 Hz, 3 H), 1.62 (m, 3 H), 1.82 (m, 1 H), 2.07 (m, 1 H), 2.62 (dd, J=14.24, 10.85 Hz, 1 H), 2.81 (dd, J=13.56, 6.78 Hz, 1 H), 3.18 (m, 2 H), 3.56 (d, J=17.97 Hz, 1 H), 3.61 (d, J=3.05 Hz, 1 H), 3.82 (m, 1 H), 3.90 (d, J=10.85 Hz, 1 H), 4.22 (m, 1 H), 4.38 (d, J=6.78 Hz, 2 H), 4.65 (m, 2 H), 6.10 (d, J=9.49 Hz, 1 H), 7.03 (m, 8 H), 7.18 (m, 1 H), 7.31 (m, 2 H), 7.36 (m, 2 H), 7.53 (m, 1 H), 7.66 (s, 1 H) Example 827
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.78 Hz, 3 H), 0.84 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.44 Hz, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.86 (m, 1 H), 2.08 (m, 1 H), 2.70 (dd, J=14.07, 10.68 Hz, 1 H), 2.82 (m, 1 H), 2.98 (m, 2 H), 3.05 (m, 2 H), 3.18 (m, 1 H), 3.32 (d, J=17.97 Hz, 1 H), 3.88 (d, J=10.85 Hz, 2 H), 4.25 (m, 1 H), 4.40 (s, 1 H), 4.57 (m, 2 H), 6.12 (d, J=9.49 Hz, 1 H), 7.03 (dd, J=8.14, 2.03 Hz, 1 H), 7.11 (m, 6 H), 7.16 (d, J=2.37 Hz, 1 H), 7.37 (m, 1 H), 7.53 (d, J=1.70 Hz, 1 H), 7.94 (d, J=1.70 Hz, 1 H) Example 828
Η NMR (300 MHz, CDC13) δ ppm 0.81 (dd, J=8.99, 6.61 Hz, 6 H), 0.88 (d, J=6.44 Hz, 3 H), 0.95 (d, J=6.44 Hz, 3 H), 1.83 (d, J=7.46 Hz, 1 H), 2.09 (m, 1 H), 2.29 (d, J=6.78 Hz, 3 H), 2.70 (dd, J=14.24, 10.51 Hz, 1 H), 2.78 (m, 1 H), 2.92 (d, J=2.37 Hz, 1 H), 2.99 (m, 2 H),
3.08 (m, 1 H), 3.20 (m, 1 H), 3.31 (d, J=17.63 Hz, 1 H), 3.61 (d, J=17.97 Hz, 1 H), 3.83 (m, 2 H), 4.24 (s, 1 H), 4.66 (m, 2 H), 5.60 (s, 1 H), 5.94 (s, 2 H), 6.05 (d, J=9.49 Hz, 1 H), 6.85 (m, 1 H), 7.14 (s, 5 H), 7.51 (dd, J=8.48, 2.37 Hz, 1 H), 7.55 (s, 1 H) Example 829
Η NMR (300 MHz, CDC13) δ ppm 0.84 (t, J=6.27 Hz, 6 H), 0.88 (m, 3 H), 0.94 (d, J=6.44 Hz, 3 H), 1.82 (d, J=8.14 Hz, 1 H), 2.11 (s, 1 H), 2.71 (dd, J=14.07, 10.68 Hz, 1 H), 2.82 (m, 1 H), 2.97 (m, 1 H), 3.05 (m, 2 H), 3.11 (d, J=4.41 Hz, 1 H), 3.19 (m, 2 H), 3.40 (d, J=18.31 Hz, 1 H), 3.64 (s, 1 H), 3.71 (d, J=17.97 Hz, 1 H), 3.84 (s, 1 H), 3.92 (d, J=10.85 Hz, 1 H), 4.25 (d, J=9.83 Hz, 1 H), 5.06 (m, 2 H), 6.15 (d, J=9.16 Hz, 1 H), 7.04 (dd, J=8.31, 2.20 Hz, 1 H), 7.16 (m, 5 H), 7.37 (m, 1 H), 7.44 (m, 1 H), 7.83 (d, J=8.14 Hz, 1 H), 7.97 (d, J=7.46 Hz, 1 H)
Example 830
Η NMR (300 MHz, CDC13) δ ppm 0.83 (m, 6 H), 0.88 (d, J=6.78 Hz, 3 H), 0.95 (d, J=6.78 Hz, 3 H), 1.83 (s, 1 H), 2.10 (s, 1 H), 2.30 (s, 3 H), 2.76 (m, 2 H), 2.91 (m, 1 H), 2.98 (m, 2 H), 3.06 (s, 1 H), 3.18 (d, J=8.48 Hz, 1 H), 3.41 (d, J=17.97 Hz, 1 H), 3.68 (m, 1 H), 3.82 (d, J=3.39 Hz, 1 H), 3.86 (d, J=10.85 Hz, 1 H), 4.28 (s, 1 H), 5.00 ( , 2 H), 6.08 (m, 2 H), 6.53 (s, 2 H), 6.85 (d, J=8.14 Hz, 2 H), 7.18 (m, 5 H), 7.51 (m, 1 H), 7.59 (m, 1 H) Example 831
Η NMR (300 MHz, CDC13) δ ppm 0.71 (d, J=6.44 Hz, 3 H), 0.79 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 1.87 (m, 1 H), 2.09 (m, 1 H), 2.75 (dd, J=14.07, 10.68 Hz, 1 H), 2.91 (m, 2 H), 3.08 (dd, J=14.07, 4.24 Hz, 1 H), 3.15 (m, 2 H), 3.50 (d, J=17.97 Hz, 1 H), 3.74 (m, 1 H), 3.93 (s, 3 H), 3.97 (d, J=10.85 Hz, 1 H), 4.10 (s, 1 H), 4.30 (m, 1 H), 4.45 (s, 2 H), 4.94 (m, 2 H), 6.49 (d, J=9.16 Hz, 1 H), 7.04 (dd, J=8.31, 2.20 Hz, 1 H), 7.13 (m, 7 H), 7.35 (d, J=8.48 Hz, 1 H), 7.90 (dd, J=7.97, 1.53 Hz, 1 H), 8.36 (dd, J=4.92, 1.53 Hz, 1 H) Example 832
Η NMR (300 MHz, CDC13) δ ppm 0.75 (d, J=6.78 Hz, 3 H), 0.81 (d, J=6.44 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.94 (t, J=6.44 Hz, 3 H), 1.80 (dd, J=14.58, 7.80 Hz, 2 H), 2.05 (m, 1 H), 2.29 (s, 3 H), 2.64 (dd, J=14.07, 10.68 Hz, 1 H), 2.77 (m, 1 H), 3.04 (m, 1 H), 3.18 (m, 2 H), 3.53 (d, J=17.97 Hz, 1 H), 3.78 (m, 1 H), 3.85 (d, J=10.85 Hz, 1 H), 4.21 (q, J=7.12 Hz, 1 H), 4.52 (m, 2 H), 5.93 (m, 2 H), 6.07 (d, J=9.49 Hz, 1 H), 6.76 (d, J=8.14 Hz, 1 H), 6.87 (d, J=8.48 Hz, 1 H), 6.91 (m, 2 H), 7.03 (m, 5 H), 7.50 (dd, J=8.48, 2.37 Hz, 1 H), 7.55 (d, J=2.03 Hz, 1 H), 8.02 (s, 2 H) Example 833 Η NMR (300 MHz, CD3OD) δ ppm 0.79 (d, J=6.44 Hz, 3 H), 0.83 (d, J=6.44 Hz, 3 H), 0.86 (d, J=6.44 Hz, 3 H), 0.89 (d, J=6.78 Hz, 3 H), 2.01 (m, 2 H), 2.50 (dd, J=13.73, 11.70 Hz, 1 H), 2.86 (dd, J=13.56, 6.78 Hz, 1 H), 2.99 (m, 2 H), 3.11 (d, J=17.97 Hz, 1 H), 3.22 (dd, J=13.90, 3.39 Hz, 1 H), 3.38 (dd, J=14.92, 3.73 Hz, 1 H), 3.78 (m, 2 H), 3.96 (s, 3 H), 4.02 (d, J=10.85 Hz, 1 H), 4.16 (m, 1 H), 4.97 (m, 2 H), 6.90 (m, 2 H), 7.00 (m, 3 H), 7.16 (m, 2 H), 7.24 (m, 1 H), 7.31 (m, 1 H), 7.52 (d, J=7.80 Hz, 1 H), 7.59 (d, J=7.46 Hz, 1 H), 7.65 (m, 2 H), 7.89 (s, 1 H) Example 834 Η NMR (300 MHz, CDC13) δ ppm 0.83 (m, 6 H), 0.88 (d, J=6.78 Hz, 3 H), 0.95 (d, J=6.44 Hz, 3 H), 1.80 (s, 1 H), 2.10 (s, 1 H), 2.30 (s, 3 H), 2.73 (dd, J=14.24, 10.51 Hz, 1 H), 2.80 (m, 1 H), 2.95 (d, J=4.41 Hz, 3 H), 3.02 (m, 2 H), 3.17 (m, 1 H), 3.39 (d, J=17.63 Hz, 1 H), 3.69 (d, J=17.97 Hz, 1 H), 3.83 (s, 1 H), 3.87 (d, J=10.85 Hz, 1 H), 4.16 (d, J=14.92 Hz, 1 H), 4.80 (s, 2 H), 6.13 (s, 1 H), 6.63 (s, 1 H), 6.89 (m, 1 H), 6.98 (s, 1 H), 7.04 (s, 1 H), 7.14 (s, 5 H), 7.50 (dd, J=8.48, 2.03 Hz, 1 H), 7.55 (d, J=2.03 Hz, 2 H) Example 835
Η NMR (300 MHz, CDC13) δ ppm 0.78 (d, J=6.44 Hz, 6 H), 0.90 (d, J=6.44 Hz, 6 H), 1.86 (s, 2 H), 2.12 (s, 2 H), 2.30 (s, 3 H), 2.60 (s, 3 H), 2.85 (m, 2 H), 3.07 (m, 3 H), 3.38 (d, J=17.97 Hz, 1 H), 3.66 (d, J=18.31 Hz, 1 H), 3.86 (s, 2 H), 4.17 (m, 1 H), 4.69 (s, 2 H), 6.46 (s, 1 H), 6.94 (m, 1 H), 7.12 (s, 6 H), 7.34 (s, 1 H), 7.44 (d, J=7.12 Hz, 1 H), 7.49 (s, 1 H) Example 836
Η NMR (300 MHz, CDC13) δ ppm 0.70 (d, J=6.44 Hz, 3 H), 0.75 (d, J=6.44 Hz, 3 H), 0.91 (m, 6 H), 1.90 (m, 2 H), 2.08 (m, 2 H), 2.24 (s, 3 H), 2.79 (m, 1 H), 3.07 (m, 2 H), 3.57 (d, J=18.31 Hz, 1 H), 3.70 (m, 1 H), 4.12 (m, 1 H), 4.18 (d, J=10.51 Hz, 1 H), 4.27 (t, J=10.17 Hz, 1 H), 4.74 (s, 2 H), 6.83 (s, 1 H), 7.05 (dd, J=8.31, 2.20 Hz, 3 H), 7.11 (m, 5 H), 7.22 (m, 2 H), 7.37 (m, 1 H), 8.02 (s, 1 H) Example 837
Η NMR (300 MHz, CDC13) δ ppm 0.70 (d, J=6.44 Hz, 3 H), 0.75 (d, J=6.44 Hz, 3 H), 0.88 (d, J=6.78 Hz, 3 H), 0.91 (m, 3 H), 1.90 (m, 2 H), 2.08 (m, 2 H), 2.24 (s, 3 H), 2.78 (m, 2 H), 3.04 (m, 2 H), 3.11 (m, 1 H), 3.63 (m, 2 H), 4.12 (m, 1 H), 4.18 (d, J=10.51 Hz, 1 H), 4.27 (t, J=10.17 Hz, 1 H), 4.74 (s, 2 H), 6.83 (s, 1 H), 7.05 (dd, J=8.31, 2.20 Hz, 2 H), 7.11 (m, 6 H), 7.22 (m, 2 H), 7.37 (m, 1 H), 8.02 (s, 1 H) Example 838 Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.44 Hz, 3 H), 0.87 (m, 6 H), 0.94 (d, J=6.44 Hz, 3 H), 1.81 (d, J=6.78 Hz, 2 H), 2.06 (m, 1 H), 2.30 (d, J=3.05 Hz, 3 H), 2.71 (m, 1 H), 2.79 (m, 1 H), 3.07 (m, 1 H), 3.19 (m, 1 H), 3.40 (d, J=17.97 Hz, 1 H), 3.65 (d, J=17.97 Hz, 1 H), 3.87 (m, 2 H), 4.29 (d, J=18.31 Hz, 2 H), 4.62 (m, 2 H), 6.14 (d, J=9.16 Hz, 1 H), 6.87 (d, J=8.48 Hz, 1 H), 7.11 (m, 3 H), 7.22 (m, 2 H), 7.48 (m, 2 H), 7.58 (m, 1 H), 7.66 (s, 1 H), 8.02 (s, 1 H), 8.68 (d, J=4.75 Hz, 1 H) Example 839
Η NMR (300 MHz, CDC13) δ ppm 0.80 (d, J=6.78 Hz, 3 H), 0.83 (d, J=6.78 Hz, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.95 (d, J=6.44 Hz, 3 H), 1.83 (s, 1 H), 2.09 (d, J=10.51 Hz, 1 H), 2.30 (d, J=3.73 Hz, 4 H), 2.70 (s, 3 H), 2.79 (dd, J=13.56, 6.44 Hz, 1 H), 3.02 (m, 2 H), 3.19 (m, 1 H), 3.33 (d, J=17.97 Hz, 1 H), 3.64 (d, J=17.97 Hz, 1 H), 3.86 (m, 2 H), 4.32 (d, J=17.63 Hz, 1 H), 4.68 (m, 2 H), 5.71 (s, 1 H), 6.13 (d, J=9.16 Hz, 1 H), 6.86 (d, J=8.48 Hz, 1 H), 7.10 (m, 5 H), 7.23 (m, 2 H), 7.41 (m, 1 H), 7.54 (m, 1 H), 7.56 (m, 1 H), 7.96 (m, 1 H), 8.02 (s, 1 H)
Example 840
Η NMR (300 MHz, CDC13) δ ppm 0.77 (d, J=6.78 Hz, 3 H), 0.80 (d, J=6.78 Hz, 3 H), 0.89 (d, J=6.78 Hz, 3 H), 0.93 (d, J=6.78 Hz, 3 H), 1.83 (m, 1 H), 2.07 (m, 1 H), 2.62 (dd, J=14.07, 10.68 Hz, 1 H), 2.83 (dd, J=13.39, 6.95 Hz, 1 H), 2.91 (d, J=13.22 Hz, 1 H), 3.01 (m, 2 H), 3.17 (m, 1 H), 3.56 (d, J=17.97 Hz, 1 H), 3.66 (s, 1 H), 3.83 (s, 1 H), 3.89 (d, J=10.51 Hz, 1 H), 4.20 (m, 1 H), 4.41 (s, 1 H), 4.63 (s, 2 H), 4.69 (s, 2 H), 6.27 (d, J=9.83 Hz, 1 H), 7.01 (m, 2 H), 7.06 (m, 5 H), 7.16 (d, J=2.03 Hz, 1 H), 7.24 (s, 1 H), 7.29 (d, J=5.09 Hz, 1 H), 7.33 (m, 2 H), 7.36 (d, J=8.48 Hz, 1 H), 7.43 (s, 1 H) Example 841 Η NMR (300 MHz, CDC13) δ ppm 0.65 (d, J=6.44 Hz, 3 H), 0.81 (m, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.92 (m, 3 H), 1.23 (m, 2 H), 1.89 (m, 2 H), 2.21 (s, 3 H), 2.75 (m, 1 H), 2.81 (m, 1 H), 2.95 (m, 2 H), 3.05 (m, 2 H), 3.11 (m, 1 H), 3.67 (s, 2 H), 4.12 (q, J=7.35 Hz, 1 H), 4.25 (m, 2 H), 4.53 (s, 1 H), 4.70 (m, 2 H), 6.80 (s, 1 H), 6.93 (s, 1 H), 7.04 (m, 1 H), 7.12 (m, 5 H), 7.21 (d, J=2.03 Hz, 1 H), 7.38 (m, 1 H) Example 842
Η NMR (300 MHz, CDC13) δ ppm 0.74 (d, J=6.44 Hz, 3 H), 0.86 (m, 6 H), 0.92 (d, J=6.44 Hz, 3 H), 1.01 (m, 1 H), 1.37 (m, 1 H), 1.83 (m, 1 H), 1.93 (d, J=16.95 Hz, 1 H), 2.70 (dd, J=14.07, 10.68 Hz, 1 H), 2.83 (dd, J=13.22, 6.78 Hz, 1 H), 2.90 (d, J=8.48 Hz, 1 H), 2.96 (m, 1 H), 3.05 (m, 1 H), 3.42 (d, J=17.97 Hz, 1 H), 3.70 (d, J=17.63 Hz, 1 H), 3.77 (d, J=2.71 Hz, 1 H), 3.87 (m, 3 H), 4.04 (m, 1 H), 4.24 (m, 1 H), 4.42 (s, 2 H), 4.90 (m, 2 H), 6.31 (d, J=9.16 Hz, 1 H), 6.85 (t, J=2.71 Hz, 1 H), 7.03 (dd, J=8.48, 2.03 Hz, 1 H), 7.08 (dd, J=8.99, 2.54 Hz, 1 H), 7.14 (m, 5 H), 7.17 (d, J=2.03 Hz, 1 H), 7.20 (m, 1 H), 7.35 (d, J=8.14 Hz, 1 H), 7.75 (m, 1 H), 7.85 (m, 1 H) Example 843 Η NMR (300 MHz, CDC13) δ ppm 0.79 (d, J=6.44 Hz, 3 H), 0.84 (m, 3 H), 0.88 (d, J=6.44 Hz, 3 H), 0.93 (d, J=6.78 Hz, 3 H), 1.22 (m, 1 H), 1.86 (m, 2 H), 2.68 (dd, J=14.24, 10.85 Hz, 1 H), 2.82 (dd, J=13.22, 6.78 Hz, 1 H), 3.02 (m, 3 H), 3.18 (m, 1 H), 3.40 (m, 1 H), 3.63 (d, J=17.97 Hz, 2 H), 3.84 (m, 1 H), 4.00 (d, J=10.85 Hz, 1 H), 4.27 (m, 1 H), 4.39 (s, 2 H), 5.08 (m, 2 H), 6.16 (d, J=9.49 Hz, 1 H), 7.06 (m, 7 H), 7.17 (m, 1 H), 7.36 (m, 2 H), 7.64 (m, 1 H), 7.76 (m, 1 H), 8.15 (d, J=7.46 Hz, 1 H), 8.28 (d, J=7.46 Hz, 1 H), 8.88 (d, J=4.41 Hz, 1 H) Example 844 Η NMR (300 MHz, DMSO-d6) δ ppm 0.70 (m, 6 H), 0.85 (m, 1 H), 1.17 (t, J=7.12 Hz, 4 H), 1.24 (d, J=3.05 Hz, 1 H), 1.50 (m, 6 H), 1.94 (m, 1 H), 2.23 (s, 1 H), 2.36 (m, 1 H), 2.59 (s, 3 H), 2.73 (s, 1 H), 2.88 (d, J=6.78 Hz, 1 H), 2.95 (m, 1 H), 3.03 (m, 1 H), 3.09 (m, 1 H), 3.19 (m, 2 H), 3.31 (m, 1 H), 3.76 (d, J=17.97 Hz, 1 H), 3.90 (s, 1 H), 4.01 (m, 1 H), 4.64 (s, 2 H), 6.99 (m, 3 H), 7.07 (m, 2 H), 7.24 (s, 1 H), 7.79 (s, 2 H), 7.95 (m, 3 H), 8.24 (d, J=9.49 Hz, 1 H), 8.85 (s, 1 H)
The foregoing is merely illustrative ofthe invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scoped ofthe nature ofthe invention which are defined in the appended claims.

Claims

WHAT IS CLAIMED IS
A compound of formul
Figure imgf000372_0001
or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, wherein:
Figure imgf000372_0002
X is O, S orNH;
Y is O, S orNH;
R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl or heteroarylalkyl; wherein each R is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, formyl, nitro, hydroxy, alkoxy, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, haloalkyl, hydroxyalkyl and alkoxyalkyl;
Ri is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rla)NRaRb or -OC(=O)C(H)(Rla)N(H)C(O)ORa;
Rla is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each Rla is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaRb, -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Ra)SO2NRaRb, -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaRb and -C(=O)ORa;
R2 is H;
R3 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra, -alkylNRaRb, -alkylN(Rb)C(=O)ORa, -alkylN(Rb)C(=O)Ra, -alkylN(R )SO2Ra or -alkylN(Rb)SO2NRaRb; wherein each ofthe cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkyl moiety ofthe cycloalkylalkyl, cycloalkenyl moiety ofthe cycloalkenylalkyl, hetrocycle moiety ofthe heterocyclealkyl, heteroaryl moiety ofthe heteroarylalkyl, aryl moiety ofthe arylalkyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), - N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS (alkyl), -alkylSO2(alkyl), -alkylNH , -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2, -alkylC(=O)alkyl and R3a;
R a is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, wherein each R3a is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(all yl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2 and -alkylC(=O)alkyl;
R). is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl wherein each i is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, alkyl, oxo, alkenyl, alkynyl, nitro, cyano, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, nitroalkyl, -OR^, -SR^, -SORia, -SO2R4* -NR4aR4b, -OC(=O)R a, -C(=O)R4a, -C(=O)OR4a, -C(=O)NR4aR4b, -N(R4b)C(=O)R4a, -N(R4b)C(=O)OR4a, -N(R4b)SO2R4a, -N(R4 )C(=O)NR4aR b, -N(R4 )SO2NLR4aR4 , -alkylSR4a, -alkylSORta, -alkylSORa, -alkylN^aRn,, -alkylOC(=O)R4a, -alkylC(=O)R4a, -alkylC(=O)OR4a, -alkylC(=O)NR4aR4b, -alkylN(R4b)C(=O)R4a, -alkylN(R4b)C(=O)OR4a, -alkylN(R4b)SO2R4a, -alkylN(R4 )C(=O)NR4aR4b, -alkylN(R4b)SO2NR4aR4b, -N(H)C(=O)alkylN(H)C(=O)OI^ -N(H)C(=O)alkylNR4aR4b, -C(R4b)=NOR4a, -C(NR4aR4b)=NOR4a and -C(R4b)=NOC(=O)alkylNR4aR4 ; ja and R ,, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl and heteroalkyl; wherein each R4a and R4b, at each occurrence, is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, hydroxy, alkoxy, halo, nitro, cyano, formyl, oxo, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)alkyl, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)alkyl, -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, cyanoalkyl, nitroalkyl, formylalkyl and alkoxyalkyl;
R5 is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -OalkylSO2alkyl, -O-heterocycle, -alkyl-O-aryl or -O-alkyl-heteroaryl; wherein the heterocycle, aryl or heteroaryl moiety of -O-heterocycle, -alkyl-O-aryl and -O-alkyl-heteroaryl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl) , cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
R6 is aryl or heteroaryl; wherein each R6 is substituted with 0 or 1 substituent selected from the group consisting of -C(H)=NOH, -C(alkyl)=NOH, -C(H)=NO(alkyl), -C(alkyl)=NO(alkyl), -C(H)=NO(arylalkyl) and -C(alkyl)=NO(arylalkyl);
R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; wherein each R7 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, -OR., -OalkylC(=O)NRaR , -SRa, -SORa, -SO2Ra, -SO2NRaRb, -C(=O)Ra, -NRaR , -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Rb)SO2NRaRb, -N(Rb)C(=NH)NRaRb, -N(R )C(=O)NRaRb, -C(=O)NRaR , -C(=O)ORa and R7a;
R7a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R7a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2;
R8 is -C(=O)OR8a or -C(=O)alkylNR8aR8 ,
R8a and R8b are, at each occurrence, independently selected from the group consisting of alkyl, arylalkyl and heteroarylalkyl; wherein each R8a and R8b is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of alkyl, nitro, hydroxy, alkoxy, amino, formyl, halo, haloalkyl, hydroxyalkyl, alkoxyalky aminoalkyl and formylalkyl;
R9 is alkyl, alkenyl, alkynyl, -C(=O)NRaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R9 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb, -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaR , -N(R )SO2NRaRb, -C(=O)Ra, -C(=O)NRaR , -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaR , -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(alkyl)=NNRaRb, -C(H)(=NORa)NRaRb, -C(alkyl)(=NORa)NRaR , -alkylN(R )NRaRb, -alkylN(R )C(=O)Ra, -alkylN(R )C(=O)ORa, -alkylN(Rb)C(=O)NRaRb, -alkylN(Rb)SO2NRaRb, -alkylN(R )SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaRb and R9a;
R a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R9a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -afkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
R10 is alkyl, alkenyl, alkynyl, -C(=O)NRaR , -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R10 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SOR,, -SO2Ra,-SO2NRa, -SO2ORa, -NRaR , -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaRb, -N(Rb)SO2NRaRb, -C(=O)Ra, -C(=O)NRaR , -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(alkyl)=NNRaRb, -C(H)(=NORa)NRaR , -C(alkyl)(=NORa)NRaR , -alkylN(Rb)NRaRb, -alkylN(R )C(=O)Ra, -alkylN(Rb)C(=O)ORa, -alkylN(Rb)C(=O)NRaRb, -alkylN(R )SO2NRaR , -alkylN(Rb)SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaRb and R10a;
R10a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R10a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoaikyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
Rπ is alkyl, alkenyl, alkynyl, -C(=O)NRaR , -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each Rπ is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaR , -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(R )SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaRb, -N(R )SO2NRaR , -C(=O)Ra, -C(=O)NRaR , -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -aUcylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(alkyl)=NNRaRb, -C(H)(=NORa)NRaRb, -C(alkyl)(=NORa)NRaR , -alkylN(R )NRaRb, -alkylN(Rb)C(=O)Ra, -alkylN(R )C(=O)ORa, -alkylN(Rb)C(=O)NRaR , -alkylN(R )SO2NRaRb, -alkylN(R )SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaRb and Rl la;
Rlla is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each Rlla is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
R12 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or cycloalkenylalkyl; wherein each R12 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, alkoxy cyano, nitro and halo;
R13 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R13 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb, -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaR , -N(Rb)SO2NRaRb, -C(=O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaR , -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaR , -C(alkyl)=NNRaRb, -C(H)(=NORa)NRaRb, -C(all yl)(=NORa)NRaR , -alkylN(Rb)NRaR , -alkylN(Rb)C(=O)Ra, -alkylN(Rb)C(=O)ORa, -alkylN(Rb)C(=O)NRaR , -alkylN(Rb)SO2NRaR , -alkylN(R )SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaR and R13a; Ri3a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R13a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle; wherein each Ra and Rb, at each occurrence, is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Re;
alternatively, Ra and Rb, together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and R,;
Re is aryl, heteroaryl or heterocycle; wherein each Re is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)2, -alkyl-N(H)C(=O)NH2, -alkyl-N(H)C(=O)N(H)(alkyl), -alkyl-N(H)C(=O)N(alkyl)2, -alkyl-C(=O)OH, -alkyl-C(=O)Oalkyl, -alkyl-C(=O)NH2, -alkyl-C(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2; and
n is 1 or 2.
2. The compound of claim 1 wherein R1 is OH and R2 is H.
3. The compound of claim 1 wherein R\ is OH, R is H, X is O, Y is O, and R3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra or -alkylNRaR .
4. The compound of claim 1 wherein R\ is OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkylalkyl and R is aryl or heteroaryl.
5. The compound of claim 1 wherein R\ is OH, R2 is H, R3 is alkyl or cycloalkylalkyl, X is O, Y is O, and R is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OR^, -NR4aR4b and -C(R4b)=NOR4a; wherein ja and (b are independently selected from the group consisting of hydrogen and alkyl.
6. The compound of claim 1 or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, selected from the group consisting of hexahyc ofuro[2,3-b]furan-3-yl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; tetrahydro-3-furanyl (lS,2R)-l-benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}acetamide; N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-(2,6- dimethylphenoxy)acetamide; (3aS,7aR)-hexahydro-4H-furo[2,3-b]pyran-3-yl (lS,2R)-l-benzyl-2-hydroxy-3-[({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate and (3aR,7aS)-hexahydro-4H-furo[2,3-b]pyran-3-yl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; 3-furylmethyl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; 2-pyridinylmethyl 2-({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)-2- oxoethylcarbamate; 2-(methylsulfonyl)ethyl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; (3aS,7aR)-hexahydro-4H-furo[2,3-b]pyran-3-yl (lS,2R)-l-benzyl-2-hydroxy-3-[({4- [(E)-(hydroxyimino)methyl]ρhenyl}sulfonyl)(isobutyl)amino]propylcarbamate; (3aR,7aS)-hexahydro-4H-furo[2,3-b]pyran-3-yl (lS,2R)-l-benzyl-2-hydroxy-3-[({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; 3-pyridinylmethyl (1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; 4-pyridinylmethyl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; l,3-thiazol-5-ylmethyl (lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylcarbamate; and N-{(2R,3S)-2-hydroxy-3-[({4-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-4- phenylbutyl}-4-[(E)-(hydroxyimino)methyl]-N-isobutylbenzenesulfonamide.
7. The compound of claim 1 having formula (II)
Figure imgf000380_0001
(II) or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, wherin
R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl or heteroarylalkyl; wherein each R is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, formyl, nitro, hydroxy, alkoxy, -ΝH2, -N(H)alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, haloalkyl, hydroxyalkyl and alkoxyalkyl; Rj is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rla)NRaRb or -OC(=O)C(H)(Rla)N(H)C(O)ORa;
Rla is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each Rla is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaR , -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Ra)SO2NRaRb, -N(R )C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaRb and -C(=O)ORa;
R2 is H;
R3 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra, -alkylNRaRb, -alkylN(Rb)C(=O)ORa, -alkylN(Rb)C(=O)Ra, -alkylN(Rb)SO2Ra or -alkylN(Rb)SO2NRaRb; wherein each ofthe cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkyl moiety ofthe cycloalkylalkyl, cycloalkenyl moiety ofthe cycloalkenylalkyl, hetrocycle moiety ofthe heterocyclealkyl, heteroaryl moiety ofthe heteroarylalkyl, aryl moiety ofthe arylalkyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), - N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS (alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2, -alkylC(=O)alkyl and R3a;
R3a is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, wherein each R3a is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2 and -alkylC(=O)alkyl;
Rt is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl wherein each Rt is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, alkyl, oxo, alkenyl, alkynyl, nitro, cyano, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, nitroalkyl, -ORta, -SRta, -SORta, -SO2Rta, -NT a ib, -OC(=O)R a, -C(=O)R4a, -C(=O)ORta, -C(=O)NR4aR4b, -N(R4b)C(=O)R4a, -N(R4b)C(=O)OR4a, ^(Rt^SQz ta,
Figure imgf000382_0001
-N(R4b)SO2NR4aR4b, -alkylSRta, -alkylSORta, -alkylSO2R4a, -alkylNRΛb, -alkylOC(=O)Rta, -alkylC(=O)Rta,
Figure imgf000382_0002
-alkylN(R4b)C(=O)R4a, -alkylN(R4b)C(=O)OR4a, -alkylN(R4b)SO2R4a, -alkylN(R4b)C(=O)Nl taR4b, -alkylN(R4b)SO2NR4aR b, -N(H)C(=O)alkylN(H)C(=O)OR4a,
Figure imgf000382_0003
-C(R4b)=NOC(=O)alkylNR4aR4b;
Rta and Rtb, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl and heteroalkyl; wherein each R^ and tb, at each occurrence, is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, hydroxy, alkoxy, halo, nitro, cyano, formyl, oxo, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)alkyl, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)alkyl, -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, cyanoalkyl, nitroalkyl, formylalkyl and alkoxyalkyl;
R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; wherein each R7 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, -ORa, -OalkylC(=O)NRaRb, -SRa, -SORa, -SO2Ra, -SO2NRaR , -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Rb)SO2NRaRb, -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaRb, -C(=O)ORa and R7a;
R7a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH , -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2;
R8 is -C(=O)OR8a or -C(=O)alkylNR8aR8b,
R8a and R8b are, at each occurrence, independently selected from the group consisting of alkyl, arylalkyl and heteroarylalkyl; wherein each R8a and R8b is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of alkyl, nitro, hydroxy, alkoxy, amino, formyl, halo, haloalkyl, hydroxyalkyl, alkoxyalky aminoalkyl and formylalkyl;
Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle; wherein each Ra and Rb, at each occurrence, is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Rc;
alternatively, Ra and Rb, together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -allcylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Rc; and
Re is aryl, heteroaryl or heterocycle; wherein each Re is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)2, -alkyl-N(H)C(=O)NH2, -alkyl-N(H)C(=O)N(H)(alkyl), -alkyl-N(H)C(=O)N(alkyl)2, -alkyl-C(=O)OH, -alkyl-C(=O)Oalkyl, -alkyl-C(=O)NH2, -alkyl-C(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2.
8. The compound of claim 7 wherein R\ is OH and R2 is H.
9. The compound of claim 7 wherein Ri is OH, R2 is H and R3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra or -alkylNRaRb.
10. The compound of claim 7 wherein R\ is OH, R2 is H, R3 is alkyl or cycloalkyl and R4 is aryl or heteroaryl.
11. The compound of claim 7 wherein Ri is OH, R2 is H, R3 is alkyl or cycloalkylalkyl and Rt is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -NR aR b and -C(Rtb)=NORta; wherein R^ and R<tb are independently selected from the group consisting of hydrogen and alkyl.
12. The compound of claim 7 wherein Ri is OH, R2 is H, R3 is alkyl or cycloalkylalkyl, Rt is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -NRtøRtb and -C(R4b)=NOR4a, and R7 is alkyl; wherein ta and R4b are independently selected from the group consisting of hydrogen and alkyl.
13. The compound of claim 7 or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrag, or combination thereof, selected from the group consisting of tert-butyl (lS)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2,2- dimethylpropylcarbamate; benzyl (lS)-3 -amino- 1-[( {(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-3- oxopropylcarbamate; methyl (lS)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2,2- dimethylpropylcarbamate; 2-pyridinylmethyl (lR)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- methylpropylcarbamate; 2-pyridinylmethyl (lS)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[(i4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- methylpropylcarbamate; benzyl (1S)-1 -[( {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- methylpropylcarbamate; benzyl (lS,2R)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- hydroxypropylcarbamate; tert-butyl (lS,2S)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- methylbutylcarbamate; benzyl (lS2S)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- methylbutylcarbamate; tert-butyl (lS)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-3- (methylsulfonyl)propylcarbamate; benzyl (lR)-l-[(aminosulfonyl)methyl]-2-({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)-2- oxoethylcarbamate; benzyl (1S)-1 -[( {(1S,2R)-1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-3- (methylsulfanyl)propylcarbamate; benzyl (lS)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[( {4-[(E)'- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-3- methylbutylcarbamate; benzyl (1S)-1 -[( {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2,2- dimethylpropylcarbamate; benzyl (15)-4-amino-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]butylcarba mate; benzyl (lS)-2-({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)-l-(lH-imidazol-4- ylmethyl)-2-oxoethylcarbamate; benzyl (lS)-2-({(lS,2R)-l-benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)-l-(lH-indol-3- ylmethyl)-2-oxoethylcarbamate; benzyl (lS,2R)-2-(2-amino-2-oxoethoxy)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[( {4-
[(£)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]propylcarba mate; methyl (36)-4-({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)-3- {[(benzyloxy)carbonyl]amino}-4-oxobutanoate; 2-pyridinylmethyl (lS,2S)-l-[({(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} amino)carbonyl] -2- methylbutylcarbamate; [6-(methoxymethyl)-2-pyridinyl]methyl (lS,2S)-l-[({(lS,2R)-l-benzyl-3- [(cyclopentylmethyl)( {4- [(E)-(hydroxyimino)methyl]phenyl} sulfonyl)amino]-2- hydroxypropyl}amino)carbonyl]-2-methylbutylcarbamate; [6-(methoxymethyl)-2-pyridinyl]methyl (1S)-1 -[( {(1S,2R)- 1 -benzyl-3- [(cyclopentylmethyl)({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2- hydroxypropyl}amino)carbonyl]-2,2-dimethylpropylcarbamate; (2S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)~ (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-( { [(3- fluorobenzyl)amino]acetyl}amino)-3,3-dimethylbutanamide; (2R)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-( { [(3- fluorobenzyl)amino]acetyl}amino)-3,3-dimethylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-( { [(3- fluorobenzyl)amino]acetyl}amino)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3 -methyl-2- [( { [(5 -nitro-3 - thienyl)methyl]amino}acetyl)amino]pentanamide; and benzyl (lS)-4-{[amino(imino)methyl]amino}-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-
[({4-[(E)-
(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]butylcarba mate.
14. The compound of claim 1 having formula (III)
Figure imgf000387_0001
(III) or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, wherein
X is O, S or NH;
R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl or heteroarylalkyl; wherein each R is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, formyl, nitro, hydroxy, alkoxy, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, haloalkyl, hydroxyalkyl and alkoxyalkyl;
Rj is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rla)NRaRb or -OC(=O)C(H)(Rla)N(H)C(O)ORa;
Rla is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each Rla is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaRb, -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Ra)SO2NRaRb,
Figure imgf000387_0002
-C(=O)NRaRb and -C(=O)ORa;
R is H;
R3 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra, -alkylNRaR , -alkylN(Rb)C(=O)ORa, -alkylN(R )C(=O)Ra, -alkylN(Rb)SO2Ra or -alkylN(Rb)SO2NRaRb; wherein each ofthe cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkyl moiety ofthe cycloalkylalkyl, cycloalkenyl moiety ofthe cycloalkenylalkyl, hetrocycle moiety ofthe heterocyclealkyl, heteroaryl moiety ofthe heteroarylalkyl, aryl moiety ofthe arylalkyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), - N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2, -alkylC(=O)alkyl and R3a;
R3a is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, wherein each R3a is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(O)N(alkyl) , -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2 and -alkylC(=O)alkyl;
l^t is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl wherein each Rt is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, alkyl, oxo, alkenyl, alkynyl, nitro, cyano, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, nitroalkyl, -ORta, -SRta, -SORta, -SO2Rta, -NRΛb, -OC(=O)R4a, -C(=O)Rta, -C(=O)ORta, -C(=O)NR4aRtb, -N(Rtb)C(=O)R4a, -N(R4b)C(=O)OR4a,
Figure imgf000388_0001
-N(R4 )C(=O)NR4aR4b, -N(R4b)SO2NR4aR4b, -alkylSRta, -alkylSORta, -alkylSO2Rta, -alkylNI taRtb, -alkylOC(=O)Rta, -alkylC(=O)Rta, -alkylC(=O)ORta, -alkylC(=O)NR4aR4b, -alkylN(Rtb)C(=O)Rta, -alkylN(Rtb)C(=O)ORta, -alkylN(R4b)SO2R4a,
Figure imgf000388_0002
-alkylN(R4b)SO2NR4aR4b, -N(H)C(=O)alkylN(H)C(=O)OR4a, -N(H)C(=O)alkylNR4aR4b, -C(R4b)=NOR4a, -C(NR4aR4 )=NOR4a and -C(R4b)=NOC(=O)alkylNR4aR4b; Rta and tb, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl and heteroalkyl; wherein each Rta and tb, at each occurrence, is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, hydroxy, alkoxy, halo, nitro, cyano, formyl, oxo, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)alkyl, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)alkyl, -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, cyanoalkyl, nitroalkyl, formylalkyl and alkoxyalkyl;
R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; wherein each R7 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, -ORa, -OalkylC(=O)NRaR , -SRa, -SORa, -SO2Ra, -SO2NRaRb, -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Rb)SO2NRaRb, -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaR , -C(=O)ORa and R7a;
R7a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R7a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2;
R9 is alkyl, alkenyl, alkynyl, -C(=O)NRaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R9 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaR , -N(R )NRaR , -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaRb, -N(Rb)SO2NRaRb, -C(=O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaR , -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaR , -C(alkyl)=NNRaRb, -C(H)(=NORa)NRaRb, -C(alkyl)(=NORa)NRaRb, -alkylN(Rb)NRaRb, -alkylN(R )C(=O)Ra, -alkylN(Rb)C(=O)ORa, -alkylN(Rb)C(=O)NRaR , -alkylN(Rb)SO2NRaRb, -alkylN(R )SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaRb and R9a; R9a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R9a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(al yl), -all^lN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle; wherein each Ra and Rb, at each occurrence, is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Re;
alternatively, Ra and Rb, together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH , -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -afkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Re;
Re is aryl, heteroaryl or heterocycle; wherein each Re is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)2, -alkyl-N(H)C(=O)NH2, -alkyl-N(H)C(=O)N(H)(alkyl), -alkyl-N(H)C(=O)N(alkyl)2, -alkyl-C(=O)OH, -alkyl-C(=O)Oalkyl, -alkyl-C(=O)NH2, -alkyl-C(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2; and
n is 1 or 2.
15. The compound of claim 14 wherein R\ is OH and R2 is H.
16. The compound of claim 14 wherein R is OH, R2 is H, X is O and R3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra or -alkylNRaRb.
17. The compound of claim 14 wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkyl and 4 is aryl or heteroaryl.
18. The compound of claim 14 wherein R\ is OH, R2 is H, X is O, R is alkyl or cycloalkylalkyl and Rt is phenyl.
19. The compound of claim 14 wherein R] is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl and R is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -NI ta tb and -C(R4b)=NOR4a; wherein Rta and I tb are independently selected from the group consisting of hydrogen and alkyl.
20. The compound of claim 14 wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl, I t is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -N ta tb and -C(Rtb)=NORta, and R7 is alkyl; wherein ta and tb are independently selected from the group consisting of hydrogen and alkyl.
21. The compound of claim 14, or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, selected from the group consisting of (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-(3-{[2-(methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} -2-oxoimidazolidin- 1 -yl)-3 -methylbutanamide; (2S)-N- {(1 S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-{3-[(l- methyl- 1 H-benzimidazol-2-yl)methyl] -2-oxoimidazolidin- 1 -yl} butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(5-nitro-3- thienyl)methyl]-2-oxo- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(4- quinolinylmethyl)- 1 -imidazolidinyl]butanamide; (2S)-2-(3- {[2-(acetylamino)-l ,3-thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)-N- {(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-[3-( {2- [(dimethylamino)methyl] - 1 ,3 -thiazol-4-yl} methyl)-2-oxo- 1 -imidazolidinyl] -3 - methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(tefrahydro-2-furanylmethyl)amino]propyl}-3- methyl-2- { 3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl} butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[2-(dimethylamino)ethyl]({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N- {(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(2-furylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(2-pyridinylmethyl)amino]propyl} -3-methyl-2- {3- [(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-{3-[(2,5-dimethyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3 -methyl-2- [3 -(3 - nitrobenzyl)-2-oxo- 1 -imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(3- pyridinylmethyl)- 1 -imidazolidinyl]butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(l -methyl- lH-benzimidazol-2-yl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(2-methoxyethyl)amino]propyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutyhnethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hyαLiOxypropyl}-2-(3-{[2- (methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)-3-methylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(3- pyridinylmethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(3- pyridinylmethyl)-l-imidazolidinyl]pentanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(4- pyridinylmethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(4- pyridinylmethyl)- 1 -imidazolidinyljpentanamide; (2S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(2-hydroxypropyl)amino]propyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(4- quinolinylmethyl)- 1 -imidazolidinyljpentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)[2-(2-thienyl)ethyl]amino}propyl)-3-methyl-2-{3- [(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(4- quinolinyhnethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-2-(3-{[2-(acetylamino)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N- {(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methylpentanamide; (2S,3S)-2-(3-{[2-(acetylamino)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N- {(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S,3S)-2-[3-(lH-benzimidazol-5-ylmethyl)-2-oxo-l-imidazolidinyl]-N-{(lS,2R)-l- benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)[(lS)-l-(hydroxymethyl)-2- methylpropyl] amino }propyl)-3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyl} butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl) [(IR)- 1 -(hydroxymethyl)-2- methylpropyl] amino }propyl)-3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyl}butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(4- quinolinylmethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(4-methyl- 3-pyridinyl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N- {(lS,2R)-l-benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(6-methyl- 2-pyridinyl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(2- pyridinylmethyl)- 1 -imidazolidinyl]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-(3-{[6-(methoxymethyl)- 2-pyridinyl]methyl}-2-oxo-l-imidazolidinyl)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-(3-{[6- (methoxymethyl)-2-pyridinyl]methyl}-2-oxo-l-imidazolidinyl)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(2- quinolinylmethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-(3-cyanobenzyl)-2- oxo-l-imidazolidinyl]-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-(2-oxo-3-{[2- (trifluoromethyl)- 1 ,3 -thiazol-4-yl]methyl} - 1 -imidazolidinyl)pentanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-3-[(cyclopentylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -3-methyl-2- {3-[(l - methyl- lH-benzimidazol-2-yl)methyl]-2-oxo- 1 -imidazolidinyljpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(8- quinoliny Imethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(8- quinolinylmethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobμtyl)amino]propyl} -2- {3-[(2-isopropyl- 1,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyI}-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-{3-[(2-isopropyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylpentanamide; (25)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-{3-[(2-isopropyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylbutanamide; (2S)-N- {(1S,2R)- 1 -benzyl-3-[(cyclopentyhnethyl)( (4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-{3-[(2-isopropyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-(3-{[2-(methoxymethyl)- l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -2-(3- {[2- (methoxymethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({2-[N- hydroxy ethanimidoyl] -4-pyridinyl} methyl)-2-oxo- 1 -imidazolidinyl] -3 -methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(7- quinolinylmethyl)- 1 -imidazolidinyl]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(6- quinolinylmethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-(2-oxo-3-{[2- (2-pyridinyl)- 1 ,3-thiazol-4-yl]methyl} - 1 -imidazolidinyl)pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(7- quinolinylmethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(6- quinolinylmethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({2-[(E)- (dimethylhydrazono)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]-3- methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(neopentyl)amino]propyl} -3-methyl-2- {3-[(l - methyl-lH-benzimidazol-2-yl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)[4-(2-pyridinyl)benzyl]amino}propyl)-3-methyl-2- {3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S,3S)-N- {(1S,2R)- l-benzyl-3-[(cyclopentylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-[3-({2-[(lE)-N- hydroxyethanimidoyl]-4-pyridinyl}methyl)-2-oxo-l-imidazolidinyl]-3-methylpentanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({6-[(lE)-N- hydroxyethanimidoyl]-2-pyridinyl}methyl)-2-oxo-l-imidazolidinyl]-3-methylpentanamide; (2S,3S)-2- {3 -[(6- { [acetyl(methyl)amino]methyl} -2-pyridinyl)methyl]-2-oxo- 1 - imidazolidinyl}-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-(3-{[2-(l- methylhydrazino)- 1 ,3 -thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-(2-oxo-3-{[2- (3-pyridinyl)-l,3-thiazol-4-yl]methyl}-l-imidazolidinyl)pentanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)~ (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {2-oxo-3-[(6- pyridin-2-yl-2-pyridinyl)methyl]- 1 -imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl- 4-quinolinyl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(4-methyl- 2-quinolinyl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-{3-[(6-isopropyl-2- pyridinyl)methyl]-2-oxo-l-imidazolidinyl}-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -3-methyl-2- {3-[(6- methyl-2-pyridinyl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(4- methyl-3 -pyridinyl)methyl] -2-oxo- 1 -imidazolidinyl} pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3 - { [4-(methoxymethyl)- 2-pyridinyl]methyl} -2-oxo- 1 -imidazolidinyl)-3 -methylpentanamide; (25)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3 ,3 -dimethyl-2-(2-oxo-3 - {[2-(3-pyridinyl)-l,3-thiazol-4-yl]methyl}-l-imidazolidinyl)butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-[2-oxo-3- (4-quinolinylmethyl)- 1 -imidazolidinyljbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(3- pyridinylmethyl)- 1 -imidazolidinyljpentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methylJphenyl}sulfonyl)(isobutyl)aminoJpropyl}-3,3-dimethyl-2-[2-oxo-3- (3-pyridinylmethyl)-l-imidazolidinylJbutanamide; (2S,3S)-2- {3 -[(2- { [acetyl(methyl)amino]methyl} - 1 ,3-thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyl}-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-{3-[(2- methyl-4-quinolinyl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-[2-oxo-3- (6-quinoliny Imethyl)- 1 -imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-[2-oxo-3- (7-quinolinylmethyl)- 1 -imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-(2-oxo-3- { [2-(2-pyridinyl)- 1 ,3-thiazol-4-yl]methyl} - 1 -imidazolidinyl)butanamide; {4-[(3-{(lS,2S)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- methylbutyl}-2-oxo-l-imidazolidinyl)methyl]-l,3-thiazol-2-yl}methyl acetate; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3 - { [6-(methoxymethyl)- 2-pyridinyl]methyl}-2-oxo-l-imidazolidinyl)-3,3-dimethylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3 - { [2-(methoxymethyl)- l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-3,3-dimethylbutanamide; (2S,36)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]pheriyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{2-oxo-3-[3-(3- pyridinyl)benzyl]- 1 -imidazolidinyl}pentanamide; (2S)-2-[3-({2-[(lS)-l-(acetylamino)ethyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l- imidazolidinyl]-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]ρhenyl} sulfonyl)(isobutyl)amino]propyl} -3 ,3 -dimethylbutanamide; (25)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-(3-{[2-(6- methyl-3 -pyridinyl)- 1 ,3 -thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-(2-oxo-3- {[2-(4-pyridinyi)-l,3-thiazol-4-yl]methyl}-l-imidazolidinyl)butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-(2-oxo-3- { [2-(2-thienyl)- 1 ,3-thiazol-4-yl]methyl} - 1 -imidazolidinyl)butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(2-methyl- 3 -pyridinyl)methyl] -2-oxo- 1 -imidazolidinyl} pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(6-methyl- 3-pyridinyl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; ethyl {6-[(3-{(lS,2S)-l-[({(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}amino)carbonyl]-2- methylbutyl}-2-oxo-l-imidazolidinyl)methyl]-2-pyridinyl}methyl(methyl)carbamate; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3 - { [6-(hydroxymethyl)- 2-pyridinyl]methyl} -2-oxo- 1 -imidazolidinyl)-3 ,3-dimethylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {2-oxo-3-[3- (l,3-thiazol-2-yl)benzyl]-l-imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {2-oxo-3-[3-(2- pyridinyl)benzyl]-l-imidazolidinyl}pentanamide; (2 )-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-(3-{[2-(5- methyl-3 -isoxazolyl)- 1 ,3 -thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-{3-[(3- methyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-{3-[(2,4-dimethyl-3- pyridinyl)methyl]-2-oxo- 1 -imidazolidinyl} -3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2- {3-[3-(3-furyl)benzyl]-2- oxo-l-imidazolidinyl}-3-methylpentanamide; (2S,3S)-N-{(iS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {2-oxo-3-[3-(4- pyrimidinyl)benzyl]-l-imidazolidinyl}pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2- {3-[(6-methoxy-3- pyridinyl)methyl]-2-oxo-l-imidazolidinyl}-3-methylpentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3,3-dimethyl-2-(2-oxo-3- { [2-(2-pyrazinyl)- 1 ,3-thiazol-4-yl]methyl} - 1 -imidazolidinyP/butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3 - { [6-(l -hydroxy- 1 - methylethyl)-2-pyridinyl]methyl}-2-oxo-l-imidazolidinyl)-3,3-dimethylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2- methyl-3-pyridinyl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3,3-dimethyl-2- {3-[(6- methyl-3-pyridinyl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3 ,3 -dimethyl-2-[2-oxo-3 - (4-pyridazinylmethyl)- 1 -imidazolidinyl]butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(4- pyridazinylmethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)aminoJpropyl}-3-methyl-2-[2-oxo-3-(3- pyridaziny Imethyl)- 1 -imidazolidinyljpentanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methylJphenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(3-methyl- 3H-imidazo[4,5-bJpyridin-2-yl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S)-Ν-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(Ε)- (hydroxyimino)methyljphenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl] -2-oxoimidazolidin- 1 -yl} butanamide; (2S)-N- {(1 S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[3-({2- [(methylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxoimidazolidin-l-yl]butanamide; (2S)-N- {(1 S,2R)-1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(pyrrolidin-2-ylmethyl)amino]propyl}-3-methyl-2- {3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxoimidazolidin-l-yl}butanamide; (2S)-2-[3-(3-aminobenzyl)-2-oxoimidazolidin-l-yl]-N-{(lS,2R)-l-benzyl-2- hydroxy-3-[({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3- methylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(l-oxido-3- pyridinyl)methyl]-2-oxo- 1 -imidazolidinyljpentanamide; (2S,3S)-N- {(1 S,2R)-1 -benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(l - oxidopyridin-4-yl)methyl]-2-oxoimidazolidin-l-yl}pentanamide; (2S,3S)-2-(3-{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}-2-oxoimidazolidin-l-yl)-N- {(1 S,2R)-1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S,3S)-2-(3-{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N- {(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methylpentanamide; (2S,3S)-2-(3-{[2-(aminomethyl)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N- {(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methylpentanamide; (2S,3S)-N- {(1 S,2R)-1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({2-[N- hydroxyethanimidoyl]pyridin-4-yl}methyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl]-3- methylpentanamide; (2R,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -2-[3-( {2- [(isopropylamino)methyl] - 1 ,3 -thiazol-4-yl} methyl)-2-oxo- 1 -imidazolidinyl] -3 - methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -2-[3-( {2- [(isopropylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]-3- methylpentanamide; (2S,3S)-2-(3-{3-[amino(hydroxyimino)methyl]benzyl}-2-oxo-l-imidazolidinyl)-N- {(1 S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-{3-[3- (hydroxymethyl)benzyl]-2-oxo-l-imidazolidinyl}-3-methylpentanamide; (2S,3 S)-N- {(1 S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({6- [(hydroxyimino)methyl]-2-pyridinyl}methyl)-2-oxo-l-imidazolidinyl]-2,3- dimethylpentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-(3 - { [6-(l -hydroxyethyl)- 2-pyridinyl]methyl} -2-oxo- 1 -imidazolidinyl)-3 ,3 -dimethylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2-isopropyl-l,3-thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyl} -3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo-l-imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-[2-oxo-3-(3-thienylmethyl)-l- imidazolidinyl]butanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2-ethyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4-yl]methyl}- 2-oxo-l-imidazolidinyl)-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hycrroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-[2-oxo-3-(l,3-thiazol-2-ylmethyl)-l- imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(3,5-dimethyl-l-phenyl-lH-pyrazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(5-ethyl-2-phenyl-l,3-thiazol-4-yl)methyl]-2- oxo- 1 -imidazolidinyl} -3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(5-ethyl-2-methyl-l,3-thiazol-4-yl)methyl]-2- oxo- 1 -imidazolidinyl} -3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-2- {3 - [(2, 5 -dimethyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl} -3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(5-nitro-3-thienyl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-2-[3-(l-benzothien-3-ylmethyl)-2-oxo-l-imidazolidinyl]-N-((lS,2R)-l-benzyl-2- hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3-methylbutanamide; (2S)-N-((1S,2R)- 1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(l-methyl-lH-benzimidazol-2- yl)methyl]-2-oxo- 1 -imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-3 -methyl-2- {3 - [( 1 -methyl- lH-indol-2-yl)methyl] -2- oxo- 1 -imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-[2-oxo-3-(2-quinolinylmethyl)-l- imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2-cyclopropyl-l,3-thiazol-4-yl)methyl]-2- oxo-l-imidazolidinyl}-3-methylbutanamide; (2S)-2-{3-[(2-acetyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-N-((lS,2R)-l- benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2-isobutyryl-l,3-thiazol-4-yl)methyl]-2-oxo- l-imidazolidinyl}-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2-butyryl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(5-mtro-2-thienyl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propyl)-3 -methyl-2- {3 - [(2-nitro- 1 ,3 -thiazol-4-yl)methyl] -2- oxo- 1 -imidazolidinyl}butanamide; (2ιS)-2-(3 - { [2-(azidomethyl)- 1 ,3-thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)-N- ((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2- {2-oxo-3-[(2-propionyl- 1 ,3-thiazol-4- yl)methyl]-l-imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3,3-dimethyl-2- {3-[(2 -methyl- 1 ,3-thiazol-4- yl)methyl]-2-oxo- 1 -imidazolidinyljbutanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino }propyl)-3-methy 1-2- { 3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] - 2-oxo- 1 -imidazolidinyljpentanamide; (2S)-N1-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanediamide; (4-{[3-((lS)-l-{[((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)amino]carbonyl} -2-methylpropyl)-2-oxo- 1 - imidazolidinyl]methyl}-l,3-thiazol-2-yl)methyl acetate; (2S)-N1-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljpentanediamide; (2S)-2-[3-(l-benzofuran-2-ylmethyl)-2-oxo-l-imidazolidinyl]-N-((lS,2R)-l-benzyl-2- hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3-methylbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]aminoJpropyl)-3-methyl-2-[2-oxo-3-(3-quinolinylmethyl)-l- imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino J propyl)-2- {3 - [(4-methoxy-5-nitro-3 -thienyl)methyl] -2-oxo- l-imidazolidinyl}-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino J propyl)-3 -methyl-2- [3 -( {2- [(methylsulfanyl)methyl] -1,3- thiazol-4-yl}methyl)-2-oxo- 1 -imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfony 1] amino } propy l)-2-(3 - { [2-(cyanomethyl)- 1 ,3 -thiazol-4-yl]methyl} -2- oxo-l-imidazolidinyl)-3-methylbutanamide; (2S)-2-(3- {[2-(acetylamino)- 1 ,3-thiazol-4-yl]methylJ -2-oxo- 1 -imidazolidinyl)-N- ((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]aminoJpropyl)-3- methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-2- { 3 - [(8-hydroxy-2-quinolinyl)methyl] -2-oxo- 1 - imidazolidinylJ-3-methylbutanamide; (2S,3S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-3 -methyl-2- {3 - [( 1 -methyl- lH-benzimidazol-2- yl)methyl]-2-oxo- 1 -imidazolidinyljpentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-2- {3 - [(4-methoxy-2-quinolinyl)methyl] -2-oxo- 1 - imidazolidinyl} -3 -methylbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-[2-oxo-3-(2-quinoxalinylmethyl)-l- imidazolidinyljbutanamide; (2S)-N1-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propyl)-N4-methyl-2- { 3 - [(2-methyl- 1 ,3 -thiazol-4- yl)methyl] -2-oxo- 1 -imidazolidinyl} butanediamide; (2S)-N1-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-N4-ethyl-2- { 3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] - 2-oxo-l-imidazolidinyl}butanediamide; (2S,3S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl] amino } propyl)-3 -methyl-2- [2-oxo-3 -(4-quinoliny Imethyl)- 1 - imidazolidinyljpentanamide; (2S,3S)-2-[3-(lH-benzimidazol-5-ylmethyl)-2-oxo-l-imidazolidinyl]-N-((lS,2R)-l- benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylpentanamide; (2S)-N-((lS,2R)-l-benzyl-3-{(cyclopentylmethyl)[(4- methoxyphenyl)sulfonyl] amino } -2-hydroxypropyl)-2-(3- {[2-(methoxymethyl)- 1 ,3 -thiazol-4- yljmethyl} -2-oxo- 1 -imidazolidinyl)-3-methylbutanamide; (2S,3S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-[2-oxo-3-(2-quinolinylmethyl)-l- imidazolidinyljpentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-3-{(cyclopentylmethyl)[(4- methoxyphenyl)sulfonyl]amino}-2-hydroxypropyl)-3-methyl-2-{3-[(l-methyl-lH- benzimidazol-2-yl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4-yl]methyl}- 2-oxo- 1 -imidazolidinyl)-3 -methylpentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-2- [3 -(3 -cy anobenzyl)-2-oxo- 1 -imidazolidinyl] -3 - methylpentanamide; , (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3,3-dimethyl-2-{3-[(l-methyl-lH-benzimidazol-2- yl)methyl] -2-oxo- 1 -imidazolidinyl} butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-(formylamino)-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}propanamide; (2S)-3-[(aminocarbonyl)amino]-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}propanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-(3-{[6-(methoxymethyl)-2-pyridinyl]methyl}-2- oxo-l-imidazolidinyl)-3-methylpentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-2- [3 -( {2- [( lE)-N-hydroxyethanimidoyl] -4- pyridinyl}methyl)-2-oxo-l-imidazolidinyl]-3-methylpentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-(2-oxo-3-{[2-(2-pyridinyl)-l,3-thiazol- 4-yl]methyl} - 1 -imidazolidinyl)pentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- memoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-(2-oxo-3-{[2-(3-pyridinyl)-l,3-thiazol- 4-yl]methyl} - 1 -imidazolidinyl)pentanamide; (2S)-N-((1S,2R)- 1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4-yl]methyl}- 2-oxo-l-imidazolidinyl)-3,3-dimethylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-l,3- thiazol-4-yl]methyl} - 1 -imidazolidinyl)butanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-(3-{[2-(2-methyl-l,3-thiazol-4yl)-l,3- thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)pentanamide; (2S,3S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-2-(3 - { [2-(2-ethyl-4-pyridinyl)- 1 ,3 -thiazol-4- yl]methyl} -2-oxo- 1 -imidazolidinyl)-3-methylpentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-(3-{[2-(6-methyl-3-pyridinyl)-l,3- thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)pentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3,3-dimethyl-2-{3-[(3-methyl-3H-imidazo[4,5- b]pyridin-2-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(3-methyl-3H-imidazo[4,5- b]pyridin-2-yl)methyl]-2-oxo-l-imidazolidinyl}pentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-3-{(cyclopentylmethyl)[(4- methoxyphenyl)sulfonyl]amino}-2-hydroxypropyl)-3-methyl-2-(2-oxo-3-{[2-(3-pyridinyl)- 1 ,3 -thiazol-4-yl]methyl} - 1 -imidazolidinyljpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- methoxyphenyl)sulfonyl](neopentyl)amino]propyl}-3-methyl-2-(2-oxo-3-{[2-(3-pyridinyl)- l,3-thiazol-4-yl]methyl}-l-imidazolidinyl)pentanamide; (2S)-2-(3 - { [2-(aminomethyl)- 1 ,3 -thiazol-4-yl]methyl} -2-oxo- 1 -imidazolidinyl)-N- ((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylbutanamide; (2 )-2-[3-({2-[(acetylamino)methyl]-l,3-thiazol-4-yl}methyl)-2-oxo-l- imidazolidinyl]-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-(3-{[2-(hydroxymethyl)-l,3-thiazol-4-yl]methyl}- 2-oxo- 1 -imidazolidinyl)-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino} propyl)-2- [3 -( {2- [(dimethylamino)methyl] - 1 ,3 -thiazol-4- yl}methyl)-2-oxo-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino }propyl)-3 -methyl-2- {3 - [(2- {[(methylsulfonyl)amino]methyl}-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-[3-({2-[(hyάLxOxyimino)methyl]-l,3-thiazol-4- yl}methyl)-2-oxo-l-imidazolidinyl]-3-methylbutanamide; methyl (4-{[3-((lS)-l-{[((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)amino]carbonyl}-2-methylpropyl)-2-oxo-l- imidazolidinyl]methyl} - 1 ,3 -thiazol-2-yl)methylcarbamate; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-[3-( {2-[(methylsulfonyl)methyl]- 1 ,3- thiazol-4-yl}methyl)-2-oxo- 1 -imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino }propyl)-2- [3 -( {2- [(diethylamino)methyl] - 1 ,3 -thiazol-4- yl}methyl)-2-oxo-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[2-(isopropylamino)-2-oxoethyl]-2-oxo-l- imidazolidinyl}-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propyl)-3 -methyl-2- [3 -( {2- [(methylamino)methyl] -1,3- thiazol-4-yl}methyl)-2-oxo-l-imidazolidinyl]butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-2- [3 -( {2- [N-hydroxyethanimidoyl] - 1 ,3 -thiazol-4- yl}methyl)-2-oxo-l-imidazolidinyl]-3-methylbutanamide; (2S,3S)-2-(3- {[2-(aminomethyl)-l ,3-thiazol-4-yl]methyl} -2-oxo- l-imidazolidinyl)-N- ((lS,2R)-l-benzyl-3-{(cyclopentylmethyl)[(4-methoxyphenyl)sulfonyl]amino}-2- hydroxypropyl)-3 -methylpentanamide; (2S,3S)-2-(3-{3-[amino(hydroxyimino)methyl]benzyl}-2-oxo-l-imidazolidinyl)-N- ((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylpentanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-4-hydroxy-2-{3-[(l-methyl-lH-benzimidazol-2- yl)methyl]-2-oxo- 1 -imidazolidinyl}butanamide; (2»S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -3-methyl-2- {3-[(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lR,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl} -2- {3-[(2-isopropyl- 1 ,3-thiazol-4- yl)methyl]-2-oxo- 1 -imidazolidinyl} -3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2- {3-[(2-isopropyl-l ,3-thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyl} -3- methylbutanamide; (2S)-N- { ( 1 S,2R)-3 - [ [(3 -amino-4-chlorophenyl)sulfonyl] (isobutyl)amino] - 1 -benzyl-2- hydroxypropyl}-2-{3-[(2-isopropyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-2-{3-[(2-ethyl-l,3-thiazol-4-yl)methyl]-2- oxo-l-imidazolidinyl}-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{3-[(2-ethyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2- { 3 - [(2-ethyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl} -3 - methylbutanamide; (2S)-N- {(1 S,2R)-3 - [ [(3 -amino-4-hydroxyphenyl)sulfonyl] (isobutyl)amino] - 1 -benzyl- 2-hydroxypropyl}-2-{3-[(2-ethyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4- yl]methyl} -2-oxo- 1 -imidazolidinyl)-3 -methylbutanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2-(3 - {[2-(methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} -2-oxo- 1 - imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2-(3- {[2-(methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} -2-oxo-l - imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-hydroxyphenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl} -2-(3 - { [2-(methoxymethyl)- 1 ,3 -thiazol-4-yl]methyl} -2-oxo- 1 - imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3-{[(l-methyl-lH-imidazol-4- yl)sulfonyl]amino}phenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyl}butanamide; (2S)-N- {(1S,2R)- 1 -benzyl-3-[[(3,5-dichloro-4- hydroxyphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(5-mtro-3-thienyl)methyl]- 2-oxo- 1 -imidazolidinyl}butanamide; (26)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-hydroxy-3-[(3- pyridinylsulfonyl)amino]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-hydroxy-3- [(methylsulfonyl)amino]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; ' (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-2-{3-[(2-cyclopropyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2- {3 - [(2-cyclopropyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl } -3 - methylbutanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{3-[(2-cyclopropyl-l,3-tlιiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-ethyl-4-hydroxyphenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3,5-dichloro-2- hydroxyphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl({4- [(methylsulfonyl)amino]phenyl}sulfonyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyl } butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(5-fluoro-4-hydroxy-2- methylphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(5-chloro-4-hydroxy-2- methylphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-chloro-4-hydroxy-5- methylphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- {[(methylamino)sulfonyl]amino}phenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3- [(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; ethyl 2-hydroxy-5-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanoyl)amino]-4- phenylbutyl}(isobutyl)amino]sulfonyl}phenylcarbamate; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- isoproρylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(l-methyl-lH- benzimidazol-2-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3,5- dimethylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfbnyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -3-methyl-2- {3-[(5-nitro-3-thienyl)methyl]-2-oxo- 1 - imidazolidinyl}butanamide; (2S)-N- {(1S,2R)-1 -benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfόnyl](isobutyl)amino]propyl} -3-methyl-2- {3-[(2-nitro- 1 ,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(4-amino-3-hydroxyphenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl} butanamide; {4-[(3-{(lS)-l-[({(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l- benzyl-2-hydroxypropyl}amino)carbonyl]-2-methylpropyl}-2-oxo-l-imidazolidinyl)methyl]- l,3-thiazol-2-yl}methyl acetate; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[{[4-hydroxy-3- (methylamino)phenyl]sulfonyl}(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N- {(1S,2R)- 1 -benzyl-3-[ {[3-(dimethylamino)-4- hydroxyphenyl]sulfonyl}(isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-{[(ethylamino)carbonyl]amino}-4- hydroxyphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; methyl 2-hydroxy-5- {[ {(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2- {3-[(2-methyl- 1 ,3- thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyl}butanoyl)amino] -4- phenylbutyl}(isobutyl)amino]sulfonyl}phenylcarbamate; benzyl 2-hydroxy-5-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanoyl)amino]-4- phenylbutyl}(isobutyl)amino]sulfonyl}phenylcarbamate; (2S)-N-{(lS,2R)-3-[[(l-acetyl-2,3-dihydro-lH-indol-5-yl)sulfonyl](isobutyl)amino]- 1 -benzyl-2-hydroxypropyl} -3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(2-chloro-4-hydroxy-5- methylphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(3-acetyl-4-hydroxyphenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(2-amino-l,3-thiazol-5-yl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-[2-oxo-3-(3-quinolinylmethyl)- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonylJ(isobutyl)amino]propyl}-3-methyl-2-{3-[(5-nitro-3-thienyl)methyl]-2- oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -3 -methyl-2- [2-oxo-3 -(4-quinoliny Imethyl)- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[{[4-(2- hydroxyethyl)phenyl]sulfonyl}(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-2-(3-{[2-(acetylamino)-l,3-thiazol-4-yl]methyl}-2-oxo-l-imidazolidinyl)-N- {(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-cyano-4-hydroxyphenyl)sulfonyl](isobutyl)amino]- 2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S,3S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl} -3-methyl-2- {3-[(l -methyl- lH-benzimidazol-2-yl)methyl]-2-oxo-l - imidazolidinyl}pentanamide; (2S3S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-l-imidazolidinyl]pentanamide; (2S,3S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl}-2-[3-(lH-benzimidazol-5-ylmethyl)-2-oxo-l-imidazolidinyl]-3- methylpentanamide; (2S 3S)-N- {(1 S,2R)-3 - [[(3-amino-4-chlorophenyl)sulfonyl] (isobutyl)amino]- 1 -benzyl- 2-hydroxypropyl}-3-methyl-2-[2-oxo-3-(2-quinolinylmethyl)-l-imidazolidinyl]pentanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-l,3-thiazol-4-yl]methyl}-l- imidazolidinyl)butanamide; (2S)-N-{(lS,2R)-3-[[(4-aminoρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-l,3-thiazol-4-yl]methyl}-l- imidazolidinyl)butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2-(3 - { [2-(methoxymethyl)~ 1 ,3-thiazol-4-yl]methyl} -2-oxo- 1 - imidazolidinyl)-3,3-dimethylbutanamide; (2S, 3S)-N- {(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]- 1 -benzyl- 2-hydroxypropyl}-3-methyl-2-(3-{[2-(2-methyl-l,3-thiazol-4-yl)-l,3-thiazol-4-yl]methyl}-2- oxo- 1 -imidazolidinyl)pentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(neopentyl)amino]propyl} -3-methyl-2- {3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[{[4-((E)-{[(3- aminopropanoyl)oxy]imino}methyl)phenyl]sulfonyl} (isobutyl)amino]- 1 -benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-£(1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(3- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo- 1 -imidazolidinyl} butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(4-chlorophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(4-fluorophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3,4-dibromophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl} -3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N- {(1S,2R)-1 -benzyl-3-[[(l ,2-dimethyl- lH-imidazol-4- yl)sulfonyl](isobutyl)amino]-2-hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(l-methyl-lH-imidazol-4- yl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N- {(lS,2R)-l-benzyl-3-[[(4-bromo-5-chloro-2- pyridinyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol- 4-yl)methyl]-2-oxo-l-imidazolidinylJbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(4-cyanophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinylj butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-fluorophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinylj butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(4-bromophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-chloro-4-fluorophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropylj -3-methyl-2- {3-[(2-methyl-l ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyl J butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3,4-dimethoxyphenyl)sulfonyl](isobutyl)amino]-2- hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl J butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3,4-dichlorophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropylj -3-methyl-2- {3-[(2 -methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[[(4-acetylphenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(2,4,6- trichlorophenyl)sulfonyl] amino } propy l)-3 -methyl-2- {3 - [(2-methyl- 1 ,3 -tlιiazol-4-yl)methyl] - 2-oxo-l-imidazolidinylJbutanamide; (2»S)-N-{(lS,2R)-l-benzyl-3-[[(2-cyanophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl -3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-cyanophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropylj -3-methyl-2- {3 -[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyl J butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(2,5-dichloro-3-thienyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl(2-thienylsulfonyl)amino]propyl}-3- methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(2,4-dichloroρhenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(2,3-dichlorophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropylj -3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3,5-dimethyl-4-isoxazolyl)sulfonyl](isobutyl)amino]- 2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinylj butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(2-methoxy-4- methylphenyl)sulfonyl] amino } propy l)-3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2- oxo-1-imidazolidinylJbutanamide; (2S)-N-{(lS,2R)-3-[{[4-(acetylamino)-3-chlorophenyl]sulfonylJ(isobutyl)amino]-l- benzyl-2-hydroxypropyl} -3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide; 2-hydroxy-5-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinylJbutanoyl)amino]-4- phenylbutyl J (isobutyl)amino]sulfonylJbenzoic acid; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-fluoro-4-hydroxyphenyl)sulfonyl](isobutyl)amino]- 2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl(5- isoquinolinylsulfonyl)amino]propyl} -3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2- oxo- 1 -imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(3,4,5- trimethoxyphenyl)sulfonyl]aminoJpropyl)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinylJbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(3-chloro-4-methylphenyl)sulfonyl](isobutyl)amino]-2- hydroxypropylj -3-methyl-2- {3-[(2-methyl-l ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[{[2-chloro-5- (trifluoromethyl)phenyl]sulfonyl}(isobutyl)amino]-2-hydroxypropylJ-3-methyl-2-{3-[(2- methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[{[2-chloro-4- (trifluoromethyl)phenyl]sulfonylJ(isobutyl)amino]-2-hydroxypropylJ-3-methyl-2-{3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinylJbutanamide; 4-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo-l-imidazolidinyl}butanoyl)amino]-4-phenylbutylJ(isobutyl)amino]sulfonylJbenzoic acid; (25)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl(phenylsulfonyl)amino]propyl}-3- methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(5-bromo-2-methoxyphenyl)sulfonyl](isobutyl)amino]- 2-hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(2-oxo-2,3-dihydro-l,3-benzoxazol- 6-yl)sulfonyl] amino J propyl)-3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- vinylphenyl)sulfonyl] amino } propy l)-3 -methyl-2- { 3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2- oxo- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(2,3-dihydro-l-benzofuran-5- ylsulfonyl)(isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinylJbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[{[4-(l- hydroxy ethyl)phenyl] sulfonyl J (isobutyl)amino]propyl J -3 -methyl-2- {3 - [(2-methyl- 1,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (26)-N-{(lS,2R)-3-[(l,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-l-benzyl-2- hydroxypropyl } -3 -methyl-2- { 3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[(l-benzofuran-5-ylsulfonyl)(isobutyl)amino]-l-benzyl-2- hydroxypropyl J -3 -methyl-2- {3-[(2-methyl- 1 ,3-tlιiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyljbutanamide; (26)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl(3-pyridinylsulfonyl)amino]propylJ- 3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N- {(lS,2R)-3-[ {[2-(acetylamino)-4-methyl- 1 ,3-thiazol-5- yl]sulfonylJ(isobutyl)amino]-l-benzyl-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinylJbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(2-methyl-2,3-dihydro-l- benzofuran-5 -yl)sulfonyl] amino } propy l)-3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] - 2-oxo- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(5-{(2)-[(benzyloxy)imino]methyl}-2- furyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo- 1 -imidazolidinyljbutanamide; methyl 3-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinyl}butanoyl)amino]-4- phenylbutylJ(isobutyl)amino]sulfonyl}benzoate; (2S)-N-{(lS,2R)-3-[[(3-acetylphenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(l-oxido-4- pyridinyl)sulfonyl] amino } propy l)-3 -methyl-2- { 3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(3- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2-oxo-l-imidazolidinylJbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(5-bromo-2-hydroxyphenyl)sulfonyl](isobutyl)amino]- 2-hydroxypropylJ -3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyl } butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[{[4-(l,2- dihydroxyethyl)phenyl]sulfonylJ(isobutyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinylJbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(4-formylphenyl)sulfonyl](isobutyl)amino]-2- hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[ {[4- (hydroxymethyl)phenyl] sulfonyl J (isobutyl)amino]propylJ -3-methyl-2- {3-[(2-methyl- 1,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[{[4-(formylamino)phenyl]sulfonyl}(isobutyl)amino]-2- hydroxypropyl J -3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] -2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropylj -2-(3- { [2-(hydroxymethyl)- 1 ,3-thiazol-4-yl]methyl J -2-oxo- 1 - imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[{[3-(acetylamino)-4-hydroxyphenyl]sulfonyl}(isobutyl)amino]-l- benzyl-2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; tert-butyl 2-(2-hydroxy-5-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanoyl)amino]-4- phenylbutylj (isobutyl)amino]sulfonylJ anilino)-2-oxoethylcarbamate; (2S)-N- {(1S,2R)- 1 -benzyl-3-[ {[3-(formylamino)-4- hydroxyphenyl]sulfonyl}(isobutyl)amino]-2-hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-hydroxy-3- [(phenylacetyl)amino]phenylJ sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; tert-butyl 3-(2-hydroxy-5-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanoyl)amino]-4- phenylbutyl}(isobutyl)amino]sulfonyl}anilino)-3-oxopropylcarbamate; (2S)-N- {(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl({4- [(methoxyimino)methyl]phenylJ sulfonyl)amino]propylJ -3-methyl-2- {3-[(2-methyl- 1 ,3- tliiazol-4-yl)methyl]-2-oxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(2,3-dihydro-lH-indol-5-ylsulfonyl)(isobutyl)amino]-2- hydroxypropylj -3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[[(2-amino-4-methyl-l,3-thiazol-5-yl)sulfonyl](isobutyl)amino]-l- benzyl-2-hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[({3-[(3-aminoρropanoyl)amino]-4- hydroxyphenylJsulfonyl)(isobutyl)amino]-l-benzyl-2-hydroxypropylJ-3-methyl-2-{3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l-imidazolidinylJbutanamide; tert-butyl 2-(3- {[ {(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol- 4-yl)methyl]-2-oxo-l-imidazolidinylJbutanoyl)amino]-4- phenylbutylj (isobutyl)amino] sulfonyl J anilino)-2-oxoethylcarbamate; (2S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[ {[3- (hyαLxOxymethyl)phenyl]sulfonylJ(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3- thiazol-4-yl)methyl]-2-oxo-l-imidazolidinylJbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[[(5-formyl-2-furyl)sulfonyl](isobutyl)amino]-2- hydroxypropylJ-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l- imidazolidinyl} butanamide; (2»S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({5-[(E)-(hydroxyimino)methyl]-2- furyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]- 2-oxo- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({5-[(Z)-(hydroxyimino)methyl]-2- furylJsulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo- 1 -imidazolidinyl J butanamide; (2S)-N-{(lS,2R)-3-[({4- [amino(hydroxyimino)methyl]phenylJsulfonyl)(isobutyl)amino]-l-benzyl-2-hydroxypropyl}- 3 -methyl-2- {3- [(2-methyl- 1 ,3 -thiazol-4-yl)methyl]-2-oxoimidazolidin- 1 -yl Jbutanamide; 4-{[{(2R,3S)-2-hydroxy-3-[((2S)-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]- 2-oxo-l-imidazolidinylJbutanoyl)amino]-4- phenylbutylJ(isobutyl)amino]sulfonylJbenzamide; 4-{[[(2R,3S)-2-hydroxy-3-({(2S,3S)-3-methyl-2-[2-oxo-3-(3-pyridinylmethyl)-l- imidazolidinyl]pentanoyl}amino)-4-phenylbutyl](isobutyl)amino]sulfonyl}benzamide; and (2S,3S)-N-{(lS,2R)-l-benzyl-3-[[(4-cyanophenyl)sulfonyl](isobutyl)amino]-2- hydroxypropyl}-3-methyl-2-[2-oxo-3-(3-pyridinylmethyl)-l-imidazolidinyl]pentanamide.
22. The compound of claim 1 having formula (IN)
Figure imgf000420_0001
or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, wherein
X is O, S orΝH;
R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl or heteroarylalkyl; wherein each R is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, formyl nitro, hydroxy, alkoxy, -ΝH2, -N(H)alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, haloalkyl, hydroxyalkyl and alkoxyalkyl;
Rx is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rla)NRaR or -OC(=O)C(H)(Rla)N(H)C(O)ORa;
Rla is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each Rla is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaRb, -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Ra)SO2NRaRb,
Figure imgf000420_0002
and -C(=O)ORa;
R2 is H; R3 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra, -alkylNRaRb, -alkylN(Rb)C(=O)ORa, -alkylN(Rb)C(=O)Ra, -alkylN(Rb)SO2Ra or -alkylN(Rb)SO2NRaRb; wherein each ofthe cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkyl moiety ofthe cycloalkylalkyl, cycloalkenyl moiety ofthe cycloalkenylalkyl, hetrocycle moiety ofthe heterocyclealkyl, heteroaryl moiety ofthe heteroarylalkyl, aryl moiety ofthe arylalkyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), - N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2, -alkylC(=O)alkyl and R3a;
R3a is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, wherein each R3a is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -arkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2 and -alkylC(=O)alkyl;
Rt is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl wherein each R4 is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, alkyl, oxo, alkenyl, alkynyl, nitro, cyano, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, nitroalkyl, -ORta, -SR4a, -SORta, -SO2R4a, -NRtaRtt,, -OC(=O)Rta, -C(=O)Rta, -C(=O)ORta,
Figure imgf000421_0001
Figure imgf000421_0002
-N(R4b)SO2NR4aR4b, -alkylSRa, -alkylSORta, -alkylSO2Rta, -alkylNR4aR4b, -alkylOC(=O)Rta, -alkylC(=O)R4a, -alkylC(=O)ORta, -allcylC(=O)NR4aR4b, -alkylN(R4 )C(=O)R4a, -alkylN(R4b)C(=O)OR4a, -alkylN(R4b)SO2R4a, -alkylN(R b)C(=O)NR4aR4b, -alkylN(R4b)Sθ2NR4aR4b, -N(H)C(=O)alkylN(H)C(=O)OR4a, -N(H)C(=O)alkylNR4aR4b, -C(R )=NOR4a, -C(NR4aR4b)=NOR4a and -C(R4b)=NOC(=O)alkylNR4aR4b;
Rta and Rtb, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl and heteroalkyl; wherein each R^ and Rtb, at each occurrence, is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, hydroxy, alkoxy, halo, nitro, cyano, formyl, oxo, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)alkyl, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)alkyl, -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, cyanoalkyl, nitroalkyl, formylalkyl and alkoxyalkyl;
R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; wherein each R is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, -ORa, -OalkylC(=O)NRaR , -SRa, -SORa, -SO2Ra, -SO2NRaR , -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Rb)SO2NRaRb, -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaRb, -C(=O)ORa and R7a;
R7a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R7a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)LNH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2;
R10 is alkyl, alkenyl, alkynyl, -C(=O)NRaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R10 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb, -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaRb, -N(Rb)SO2NRaRb, -C(=O)Ra, -C(=O)NRaR , -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb,
Figure imgf000422_0001
-C(alkyl)(=NORa)NRaRb, -alkylN(Rb)NRaRb, -alkylN(Rb)C(=O)Ra, -alkylN(R )C(=O)ORa, -alkylN(Rb)C(=O)NRaRb, -alkylN(Rb)SO2NRaRb, -alkylN(R )SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaRb and R10a;
R10a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R10a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle; wherein each Ra and Rb, at each occurrence, is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl) , cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Re;
alternatively, Ra and Rb, together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Rc; and Re is aryl, heteroaryl or heterocycle; wherein each Re is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkyl-N(H)(alkyl), -alkyl-N(arkyl)2, -alkyl-N(H)C(=O)NH2, -alkyl-N(H)C(=O)N(H)(alkyl), -alkyl-N(H)C(=O)N(alkyl)2, -alkyl-C(=O)OH, -alkyl-C(=O)Oalkyl, -alkyl-C(=O)NH2, -alkyl-C(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2.
23. The compound of claim 22 wherein Ri is OH and R2 is H.
24. The compound of claim 22 wherein Ri is OH, R2 is H, X is O and R3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra or -alkylNRaR .
25. The compound of claim 22 wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkyl and R4 is aryl or heteroaryl.
26. The compound of claim 22 wherein Ri is OH, R is H, X is O, R3 is alkyl or cycloalkylalkyl and Rt is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -NRtaRtb and -C(R4b)=NOR4a; wherein Rta and I tb are indepdently selected from the group consisting of hydrogen or alkyl.
27. The compound of claim 22 wherein R] is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl, t is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -O ta, -NRta t and -C(R4b)=NOR4a, and R7 is alkyl; wherein R a and tb are indepdently selected from the group consisting of hydrogen or alkyl.
28. The compound of claim 22 or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, or combination thereof, selected from the group consisting of (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenylJsulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2-oxo-2,3-dihydro-lH-imidazol-l-yl}butanamide; and (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenylJsulfonyl)(isobutyl)amino]propyl}-2-[3-({2-[N- hydroxyethanimidoyl]pyridin-4-yl}methyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl]-3- methylpentanamide.
29. The compound of claim 1 having formula (V)
Figure imgf000425_0001
(V) or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrug, salt of a prodrag, or combination thereof, wherein
X is O, S orNH;
Y is O, S orNH;
R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl or heteroarylalkyl; wherein each R is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, formyl, nitro, hydroxy, alkoxy, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, haloalkyl, hydroxyalkyl and alkoxyalkyl;
Ri is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rla)NRaR or -OC(=O)C(H)(Rla)N(H)C(O)ORa;
Rla is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each Rla is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -ORa, -SRa, -SORa, -SO2Ra, SO2Ra, -N(Ra)S
Figure imgf000425_0002
-C(=O)ORa;
R2 is H;
R3 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylallcyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra, -alkylNRaRb, -alkylN(Rb)C(=O)ORa, -alkylN(R )C(=O)Ra, -alkylN(Rb)SO2Ra or -alkylN(Rb)SO2NRaRb; wherein each ofthe cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkyl moiety ofthe cycloalkylalkyl, cycloalkenyl moiety ofthe cycloalkenylalkyl, hetrocycle moiety ofthe heterocyclealkyl, heteroaryl moiety ofthe heteroarylalkyl, aryl moiety ofthe arylalkyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), - N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2, -alkylC(=O)alkyl and R3a;
R3a is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle, wherein each R3a is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2 and -alkylC(=O)alkyl;
R is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl wherein each Rt is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, alkyl, oxo, alkenyl, alkynyl, nitro, cyano, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, nitroalkyl, -ORta, -SR4a, -SORta, -SO2Rta, - E taRtb, -OC(=O)Rta, -C(=O)R4a, -C(=O)OR4a, -C(=O)NR4aR4b, -N(R4b)C(=O)R4a, -N(R4b)C(=O)OR4a, -N SQz ta,
Figure imgf000426_0001
-N(R4 )SO2NR4aR4b, -alkylSRta, -alkylSORta, -alkylSO2Rta, -alkylNI taRth, -alkylOC(=O)Rta, -alkylC(=O)Rta, -alkylC(=O)ORta, -alkylC(=O)NR4aR4 , -alkylN(R4b)C(=O)R4a, -alkylN(R4b)C(=O)OR4a, -alkylN(Rtb)SO2Rta, -allfylN(R4b)C(=O)NR4aR4b, -alkylN(R4b)SO2NR4aR4b, -N(H)C(=O)alkylN(H)C(=O)OR4a, -N(H)C(=O)alkylNR4aRtb, -C(R4 )=NOR4a, -C(NR4aR b)=NOR4a and -C(R4 )=NOC(=O)allcylNR4aR b; ta and R^, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl and heteroalkyl; wherein each Rta and R , at each occurrence, is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, hydroxy, alkoxy, halo, nitro, cyano, formyl, oxo, -NH2, -N(H)alkyl, -N(alJcyl)2, -C(=O)alkyl, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)alkyl, -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, cyanoalkyl, nitroalkyl, formylalkyl and alkoxyalkyl;
R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; wherein each R is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, -ORa, -OalkylC(=O)NRaR , -SRa, -SORa, -SO2Ra, -SO2NRaRb, -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Rb)SO2NRaRb, -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaRb, -C(=O)ORa and R7a;
R7a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R7a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH , -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2;
Rπ is alkyl, alkenyl, alkynyl, -C(=O)NRaRb, -C(=O)ORa, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each Rπ is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SOR,, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb, -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaRb, -N(Rb)SO2NRaR , -C(=O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(alkyl)=NNRaR , -C(H)(=NORa)NRaR , -C(alkyl)(=NORa)NRaRb, -alkylN(Rb)NRaRb, -alkylN(Rb)C(=O)Ra,
Figure imgf000427_0001
-alkylN(R )SO2NRaR , -alkylN(R )SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaRb and RUa;
Riia is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each Rl la is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle; wherein each Ra and Rb, at each occurrence, is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and R,;
alternatively, Ra and Rb, together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and ReJ Re is aryl, heteroaryl or heterocycle; wherein each Re is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(afkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)2, -alkyl-N(H)C(=O)NH2, -alkyl-N(H)C(=O)N(H)(alkyl), -alkyl-N(H)C(=O)N(alkyl)2, -alkyl-C(=O)OH, -alkyl-C(=O)Oalkyl, -alkyl-C(=O)NH2, -alkyl-C(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2; and
n is 1 or 2.
30. The compound of claim 29 wherein Ri is OH and R2 is H.
31. The compound of claim 29 wherein Ri is OH, R2 is H, X is O, Y is O and R3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra or -alkylNRaR .
32. The compound of claim 29 wherein R\ is OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkyl and R4 is aryl or heteroaryl.
33. The compound of claim 29 wherein R\ is OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkylalkyl and t is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, - Rta n, and -C(R4b)=NORta; wherein Rta and tb are independently selected from the group consisting of hydrogen and alkyl.
34. The compound of claim 29 wherein R\ is OH, R2 is H, X is O, Y is O, R3 is alkyl or cycloalkylalkyl, R4 is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -ORta, -NRtaR^ and -C(Rtb)=NORta, and R is alkyl; wherein a and b are independently selected from the group consisting of hydrogen and alkyl.
35. The compound of claim 29 or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, selected from the group consisting of (2S)-N- {(1 S,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylJ-2-(3-{[2-(methoxymethyl)- 1 ,3-thiazol-4-yl]methylJ -2,4-dioxo- 1 -imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenylJ sulfonyl)(isobutyl)amino]propyl} -3 -methyl-2- [3 -(3 - nitrobenzyl)-2,4-dioxo- 1 -imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-{3-[(l-methyl- lH-benzimidazol-2-yl)methyl]-2,4-dioxo-l-imidazolidinylJbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propylJ-2-[2,4-dioxo-3-(2- quinolinylmethyl)-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenylJ sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(3-methyl- 3H-imidazo[4,5-b]pyridin-2-yl)methyl]-2,4-dioxo-l-imidazolidinylJbutanamide; (2S)-2-[3-(l,3-benzodioxol-5-ylmethyl)-2,4-dioxo-l-imidazolidinyl]-N-{(lS,2R)-l- benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylbutanamide; 2-(3-benzyl-2,4-dioxo-l-imidazolidinyl)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}acetamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[2,4-dioxo-3-(4- pyridinylmethyl)-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-[3-( {2- [(dimethylamino)methyl]-l,3-thiazol-4-yl}methyl)-2,4-dioxo-l-imidazolidinyl]-3- methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(2-methyl- l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[2,4-dioxo-3-(2- pyridiny Imethyl)- 1 -imidazolidinyl] -3 -methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2- {3-[(6-methyl- 2-pyridinyl)methyl] -2,4-dioxo- 1 -imidazolidinyl} butanamide; (2S)-2-(3-benzyl-2,4-dioxo-l-imidazolidinyl)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylbutanamide; (2S)-2-[3-(3-acetylbenzyl)-2,4-dioxo-l-imidazolidmyl]-N-{(lS,2R)-l-benzyl-2- hydroxy-3-[({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3- methylbutanamide; (25)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-(3-{[2- (methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} -2,4-dioxo-l -imidazolidinyl)-3 -methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(2- methyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (25)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-(3-{[2- (methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} -2,4-dioxo-l -imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-{3-[(2-cyano-4- pyridinyl)methyl]-2,4-dioxo-l-imidazolidinyl}-3-methylbutanamide; (2S)-2-{3-[(2-acetyl-4-pyridinyl)methyl]-2,4-dioxo-l-imidazolidinyl}-N-{(lS,2R)-l- benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylbutanamide; (2S)-2-{3-[3-(azidomethyl)benzyl]-2,4-dioxo-l-imidazolidinyl}-N-{(lS,2R)-l-benzyl- 2-hydroxy-3-[( {4-[(E)-(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3- methylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[2,4-dioxo-3-(4- pyridinylmethyl)-l-imidazolidinyl]-3-methylpentanamide; < (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[2,4-dioxo-3-(3- pyridinylmethyl)-l-imidazolidinyl]-3-methylρentanamide; (2S,3S)-2-(3-{[2-(acetylamino)-l,3-thiazol-4-yl]methyl}-2,4-dioxo-l-imidazolidinyl)- N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methylpentanamide; (2S,3S)-2-(3 - { [2-(acetylamino)- 1 ,3-thiazol-4-yl]methyl} -2,4-dioxo- 1 -imidazolidinyl)- N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[2,4-dioxo-3-(2- pyraziny Imethyl)- 1 -imidazolidinyl] -3 -methylbutanamide; (2S)-2-(3- {[2-(acetylamino)-l ,3-thiazol-4-yl]methyl} -2,4-dioxo- 1 -imidazolidinyl)-N- {(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2-(3- {3- [(methylamino)methyl]benzyl} -2,4-dioxo-l -imidazolidinyl)butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-[3-(3- nitrobenzyl)-2,4-dioxo- 1 -imidazolidinyl]pentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[2,4-dioxo-3-(4- quinolinyhnethyl)-l-imidazolidinyl]-3-methylbutanamide; (2S,3S)-2-{3-[(6-amino-2-quinolinyl)methyl]-2,4-dioxo-l-imidazolidinyl}-N- {(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S,3S)-2-{3-[(2-acetyl-4-pyridinyl)methyl]-2,4-dioxo-l-imidazolidinyl}-N-{(lS,2R)- 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S,3S)-2-(3-{[2-(acetylamino)-l,3-thiazol-4-yl]methyl}-2,4-dioxo-l-imidazolidinyl)- N- {(1S,2R)-1 -benzyl-3-[(cyclobutylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -3 -methylpentanamide; (26)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-{3-[(3- methyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -3-methyl-2- {3-[(3- methyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[2,4-dioxo-3-(2- pyridinylmethyl)-l-imidazolidinyl]-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[2,4-dioxo-3-(4- quinolinylmethyl)-l-imidazolidinyl]-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-[2,4-dioxo-3-(4- quinolinylmethyl)-l-imidazolidinyl]-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-[2,4-dioxo-3-(4- quinolinylmethyl)-l-imidazolidinyl]-3-methylpentanamide; (2S)-2-[3-(3-aminobenzyl)-2,4-dioxo-l-imidazolidinyl]-Ν-{(lS,2R)-l-benzyl-2- hydroxy-3-[( {4-[(Ε)-(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3- methylbutanamide; (2S)-N- {(1 S,2R 1 -benzyl-2-hydroxy-3-[( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-(3-{3-[N- hydroxyethanimidoyl]benzyl}-2,4-dioxo-l-imidazolidinyl)-3-methylbutanamide; (2S)-2-{3-[3-(aminomethyl)benzyl]-2,4-dioxo-l-imidazolidinyl}-N-{(lS,2R)-l- benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylbutanamide; (2S,3S)-2-[3-(3-aminobenzyl)-2,4-dioxo-l-imidazolidinyl]-N-{(lS,2R)-l-benzyl-2- hydroxy-3-[({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3- methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[3-({2-[N- hydroxy ethanimidoyl] -4-pyridinyl} methyl)-2,4-dioxo- 1 -imidazolidinyl] -3 - methylpentanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-3 -methyl-2- {3 - [(2-methyl- 1 ,3 -thiazol-4-yl)methyl] - 2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl] amino}propyl)-2-(3 - { [2-(methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} - 2,4-dioxo- 1 -imidazolidinyl)-3 -methylbutanamide; (2S)-2-(3 -benzyl-2,4-dioxo- 1 -imidazolidinyl)-N-(( 1 S,2R)- 1 -benzyl-2-hydroxy-3- {isobutyl[(4-methoxyphenyl)sulfonyl] amino } propyl)-3 -methylbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-[2,4-dioxo-3-(2-quinolinylmethyl)-l- imidazolidinyl]-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(l-methyl-lH-benzimidazol-2- yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; ethyl [3-((lS)-l-{[((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)amino]carbonyl}-2-methylpropyl)-2,5-dioxo-l- imidazolidinyl] acetate; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(3-methyl-3H-imidazo[4,5- b]pyridin-2-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[(6-methoxy-2-quinolinyl)methyl]-2,4-dioxo- 1 -imidazolidinyl} -3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-[2,4-dioxo-3-(4-quinolinylmethyl)-l- imidazolidinyl]-3-methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[(6-nitro-2-quinolinyl)methyl]-2,4- dioxo- 1 -imidazolidinyl}butanamide; (2S)-2- {3 -[(6-amino-2-quinolinyl)methyl]-2,4-dioxo- 1 -imidazolidinyl} -N-(( 1 S,2R)- 1 - benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylbutanamide; (2S)-2-(3-{[2-(acetylamino)-l,3-thiazol-4-yl]methyl}-2,4-dioxo-l-imidazolidinyl)-N- ((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylbutanamide; (2S,3S)-2-(3- {[2-(acetylamino)- 1 ,3-thiazol-4-yl]methyl}-2,4-dioxo- 1 -imidazolidinyl)- N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylpentanamide; (2S,3S)-2- {3 -[(6-amino-2-quinolinyl)methyl]-2,4-dioxo- 1 -imidazolidinyl} -N- ((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4-methoxyphenyl)sulfonyl]amino}propyl)-3- methylpentanamide; (2S,3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-[2,4-dioxo-3-(4-quinolinylmethyl)-l- imidazolidinyl]-3-methylpentanamide; (2S3S)-N-((lS,2R)-l-benzyl-3-{(cyclopentylmethyl)[(4- methoxyphenyl)sulfonyl]amino}-2-hydroxypropyl)-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4- yl]methyl} -2,4-dioxo- 1 -imidazolidinyl)-3-methylpentanamide; (2S3S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4-yl]methyl}- 2,4-dioxo-l-imidazolidinyl)-3-methylpentanamide; (2S5S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- methoxyphenyl)sulfonyl](neopentyl)amino]propyl}-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4- yl]methyl}-2,4-dioxo-l-imidazolidinyl)-3-methylpentanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[2-(isopropylamino)-2-oxoethyl]-2,4-dioxo-l- imidazolidinyl} -3 -methylbutanamide; (2S)-N-((lS,2R)-l-benzyl-2-hydroxy-3-{isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-2-{3-[2-(isobutylamino)-2-oxoethyl]-2,4-dioxo-l- imidazolidinyl} -3 -methylbutanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl]amino}propyl)-3-methyl-2-{3-[2-(4-moφholinyl)-2-oxoethyl]-2,4- dioxo-l-imidazolidinyl}butanamide; (2S)-N-((1S,2R)-1 -benzyl-2-hydroxy-3- {isobutyl[(4- methoxyphenyl)sulfonyl] amino } propy l)-2- {3 - [2-(dimethylamino)-2-oxoethyl] -2,4-dioxo- 1 - imidazolidinyl}-3-methylbutanamide; (25)-2-[3-(2-anilino-2-oxoethyl)-2,4-dioxo-l-imidazolidinyl]-N-((lS,2R)-l-benzyl-2- hydroxy-3 - {isobutyl[(4-methoxyphenyl)sulfonyl] amino } propyl)-3 -methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-2-{3-[(2-ethyl-l,3-thiazol-4-yl)methyl]- 2,4-dioxo- 1 -imidazolidinyl} -3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{3-[(2-ethyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2- { 3 - [(2-ethyl- 1 ,3 -thiazol-4-yl)methyl] -2,4-dioxo- 1 -imidazolidinyl} -3 - methylbutanamide; (25)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4- yl)methyl]-2,4-dioxo- 1 -imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-hydroxyphenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4-yl]methyl}-2,4-dioxo-l- imidazolidinyl)-3-methylbutanamide; (2S)-N- {(1S,2R)- 1 -benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl} -2-(3- {[2-(methoxymethyl)- 1 ,3-thiazol-4- yl]methyl}-2,4-dioxo-l-imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-2-(3-{[2-(methoxymethyl)-l,3-thiazol-4- yl]methyl} -2,4-dioxo- 1 -imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2-(3 - { [2-(methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} -2,4-dioxo-l - imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3'-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-(3-benzyl-2,4-dioxo-l-imidazolidinyl)-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-[3-(3-methylbenzyl)-2,4-dioxo-l-imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[3-(2-cyanobenzyl)-2,4-dioxo-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-[3-(3-nitrobenzyl)-2,4-dioxo-l-imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2- {2,4-dioxo-3-[3-(trifluoromethoxy)benzyl]- 1 -imidazolidinyl} -3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{2,4-dioxo-3-[4-(trifluoromethoxy)benzyl]-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -3-methyl-2-[3-(4-methylbenzyl)-2,4-dioxo- 1 -imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-[3-(4-nitrobenzyl)-2,4-dioxo-l-imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[2,4-dioxo-3-(2-quinolinylmethyl)-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(l-methyl-lH-benzimidazol-2-yl)methyl]-2,4-dioxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2-[3 -([ 1 , 1 '-biphenyl] -4-ylmethyl)-2,4-dioxo- 1 -imidazolidinyl]-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[3-(4-benzoylbenzyl)-2,4-dioxo-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-[3-(l-naphthylmethyl)-2,4-dioxo-l-imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-[3-(2-naphthylmethyl)-2,4-dioxo-l-imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[2,4-dioxo-3-(4-vinylbenzyl)-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -3 -methyl-2- [3 -(4-methyl-3 -nitrobenzyl)-2,4-dioxo- 1 - imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-[3-(2-nitrobenzyl)-2,4-dioxo-l-imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-[3-(2-methyl-3-nitrobenzyl)-2,4-dioxo-l- imidazolidinyljbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonylJ(isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{2,4-dioxo-3-[4-(l,2,3-thiadiazol-4-yl)benzyl]-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2-[2,4-dioxo-3 -(3 -pyridinylmethyl)- 1 -imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2-[2,4-dioxo-3 -(2-pyridinylniethyl)- 1 -imidazolidinyl]-3 -methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[2,4-dioxo-3-(4-pyridinylmethyl)-l-imidazolidinyl]-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[3-(2-methoxy-5-nitrobenzyl)-2,4-dioxo-l-imidazolidinyl]-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[3-(2-fluoro-6-nitrobenzyl)-2,4-dioxo-l-imidazolidinyl]-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-[3-(3-methyl-4-nitrobenzyl)-2,4-dioxo-l- imidazolidinyl]butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{3-[3-(methoxymethyl)benzyl]-2,4-dioxo-l-imidazolidinyl}-3- methylbutanamide; (26)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(l-methyl-lH-benzimidazol- 2-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[3-(3-bromobenzyl)-2,4-dioxo-l-imidazolidinyl]-3-methylbutanamide; (2S)-2-[3-(3-acetylbenzyl)-2,4-dioxo-l-imidazolidinyl]-N-{(lS,2R)-3-[[(3-amino-4- chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-hydroxypropyl}-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -2- {2,4-dioxo-3-[3-(2-pyrazinyl)benzyl]- 1 -imidazolidinyl} -3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chloroρhenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{2,4-dioxo-3-[3-(2-thienyl)benzyl]-l-imidazolidinyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(5-nitro-3-thienyl)methyl]-2,4-dioxo-l- imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-2-{3-[(6-chloro-l,3-benzodioxol-5- yl)methyl]-2,4-dioxo-l-imidazolidinyl}-3-methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-[3-(l,3-benzothiazol-2-ylmethyl)-2,4-dioxo-l-imidazolidinyl]-3- methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(6-nitro-l,3-benzodioxol-5- yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-2,4- dioxo- 1 -imidazolidinyl}butanamide; (2S)-2-[3-( 1 ,3 -benzodioxol-5-ylmethyl)-2,4-dioxo- 1 -imidazolidinyl]-N- {(1 S,2R)- 1 - benzyl-2-hydroxy-3-[[(4-hydroxy-3-methylphenyl)sulfonyl](isobutyl)amino]propyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4- hydroxyphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(l-methyl-lH- benzimidazol-2-yl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (25)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl] (isobutyl)amino]propyl} -2-[2,4-dioxo-3 -(2-pyridinylmethyl)- 1 - imidazolidinyl] -3 -methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(6-methyl-2- pyridinyl)methyl] -2,4-dioxo- 1 -imidazolidinyl} butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-3-methyl-2-{3-[(4-methyl-3- pyridinyl)methyl]-2,4-dioxo-l-imidazolidinyl}butanamide; (2S)-2-(3 - { [2-(acetylamino)- 1 ,3-thiazol-4-yl]methyl} -2,4-dioxo- 1 -imidazolidinyl)-N- {(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[[(4-hydroxy-3- methylphenyl)sulfonyl](isobutyl)amino]propyl}-2-{3-[(2-cyano-4-pyridinyl)methyl]-2,4- dioxo- 1 -imidazolidinyl} -3 -methylbutanamide; (2S)-2-{3- [(2-acetyl-4-pyridinyl)methyl]-2,4-dioxo- 1 -imidazolidinyl} -N- {( 1 S,2R 1 - benzyl-2-hydroxy-3-[[(4-hydroxy-3-methylphenyl)sulfonyl](isobutyl)amino]propyl}-3- methylbutanamide; (2S)-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl}-2-{3-[3-(hydroxymethyl)benzyl]-2,4-dioxo-l-imidazolidinyl}-3- methylbutanamide; (25, 3S)-2-(3- {[2-(acetylamino)- 1 ,3 -thiazol-4-yl]methyl} -2,4-dioxo- 1 -imidazolidinyl)- N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2- hydroxypropyl} -3 -methylpentanamide; (2S, 3S)-N- {(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]- 1 -benzyl- 2-hydroxypropyl}-2-{3-[(6-amino-2-quinolinyl)methyl]-2,4-dioxo-l-imidazolidinyl}-3- methylpentanamide; (2S5 )-N-{(lS,2R)-3-[[(3-amino-4-chlorophenyl)sulfonyl](isobutyl)amino]-l-benzyl- 2-hydroxypropyl}-2-[2,4-dioxo-3-(4-quinolinylmethyl)-l-imidazolidinyl]-3- methylpentanamide; and (2S)-N-{(lS,2R)-3-[{[4-((E)-{[(3- aminopropanoyl)oxy]imino}methyl)phenyl]sulfonyl}(cyclopentylmethyl)amino]-l-benzyl-2- hydroxypropyl}-3-methyl-2-{3-[(2-methyl-l,3-thiazol-4-yl)methyl]-2,4-dioxo-l- imidazolidinyl}butanamide.
36. The compound of claim 1 having formula (NI)
Figure imgf000440_0001
(Ni) or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, wherein
X is O, S orΝH;
R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl or heteroarylalkyl; wherein each R is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, formyl, nitro, hydroxy, alkoxy, -ΝH2, -N(H)alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, haloalkyl, hydroxyalkyl and alkoxyalkyl;
Ri is H and R2 is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rla)NRaRb or -OC(=O)C(H)(Rla)N(H)C(O)ORa; or
Ri is ORa, -OSO2Ra, -OSO3Ra, -OPO3Ra, -OC(=O)C(H)(Rla)NRaRb or -OC(=O)C(H)(Rla)N(H)C(O)ORa;
Rla is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each Rla is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaR , -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Ra)SO2NRaRb, -N(Rb)C(=NH)NRaRb, -N(R )C(=O)NRaRb, -C(=O)NRaR and -C(=O)ORa;
R2 is H;
R3 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra, -alkylNRaRb, -alkylN(Rb)C(=O)ORa, -alkylN(Rb)C(=O)Ra, -alkylN(Rb)SO2Ra or -alkylN(Rb)SO2NRaRb; wherein each ofthe cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkyl moiety ofthe cycloalkylalkyl, cycloalkenyl moiety ofthe cycloalkenylalkyl, hetrocycle moiety ofthe heterocyclealkyl, heteroaryl moiety ofthe heteroarylalkyl, aryl moiety ofthe arylalkyl is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), - N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2, -alkylC(=O)alkyl and R3a;
R3a is cycloalkyl, cycloalkenyl, aryl, heteroaiyl or heterocycle, wherein each R3a is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, formyl, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, -SH, -S(alkyl), -SO2(alkyl), -NH2, -N(H)(alkyl), -N(alkyl)2, -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -C(=O)OH, -C(=O)O(alkyl), -C(=O)NH2, -C(=O)N(H)(alkyl), -C(O)N(alkyl)2, -C(=O)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, formylalkyl, nitroalkyl, -alkylSH, -alkylS(alkyl), -alkylSO2(alkyl), -alkylNH2, -alkylN(H)(alkyl),' -alkylN(alkyl)2, -alkylN(H)C(=O)alkyl, -alkylN(alkyl)C(=O)alkyl, -alkylC(=O)OH, -alkylC(=O)O(alkyl), -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl), -alkylC(=O)N(alkyl)2 and -alkylC(=O)alkyl;
Rt is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl wherein each 4 is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, alkyl, oxo, alkenyl, alkynyl, nitro, cyano, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, nitroalkyl, -OR^, -SRta, -SOR^, -SO2Rta, -NR4aR4b, -OC(=O)Rta, -C(=O)R4a, -C(=O)OR4a, -C(=O)NR4aR4b, -N(R4b)C(=O)R4a, -N(R4b)C(=O)OR4a, -N(R4b)SO2R4a, -N(R4 )C(=O)NR4aR4 , -N(R4 )SO2NR4aR4b, -alkylSRta, -alkylSOR4a, -alkylSO^, -alkylNR4aR4b, -alkylOC(=O)Rta, -alkylC(=O)R4a, -alkylC(=O)ORta, -alkylC(=O)NR4aR4b,
Figure imgf000441_0001
-alkylN(R4b)SO2R4a, -alkylN(R4b)C(=O)NR4aR4b, -alkylN(R4b)SO2NR4aR4b, -N(H)C(=O)alkylN(H)C(=O)OR4a, -N(H)C(=O)alkylNR4aR4b, -C(Rtb)=NORta, -C(NR4aR4b)=NOR4a and -C(R4b)=NOC(=O)alkylNR4aR4b;
I ta and R b, at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl and heteroalkyl; wherein each ta and tb, at each occurrence, is independently substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, hydroxy, alkoxy, halo, nitro, cyano, formyl, oxo, -NH2, -N(H)alkyl, -N(alkyl)2, -C(=O)alkyl, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)alkyl, -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, cyanoalkyl, nitroalkyl, formylalkyl and alkoxyalkyl;
R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; wherein each R7 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, -ORa, -OalkylC(=O)NRaR , -SRa, -SORa, -SO2Ra, -SO2NRaRb, -C(=O)Ra, -NRaRb, -N(Rb)C(=O)Ra, -N(Rb)C(=O)ORa, -N(Rb)SO2Ra, -N(Rb)SO2NRaR , -N(Rb)C(=NH)NRaRb, -N(Rb)C(=O)NRaRb, -C(=O)NRaR , -C(=O)ORa and R7a;
R7a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R7a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH , -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2;
R12 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or cycloalkenylalkyl; wherein each R12 is substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, alkoxy cyano, nitro and halo;
R13 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R13 is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo, -ORa, -OC(=O)Ra, -SRa, -SORa, -SO2Ra,-SO2NRa, -SO2ORa, -NRaRb, -N(Rb)NRaRb, -N(Rb)C(=O)Ra, -N(Rb)SO2Ra, -N(Rb)C(=O)ORa, -N(Rb)C(=O)NRaR , -N(Rb)SO2NRaRb, -C(=O)Ra, -C(=O)NRaRb, -C(=O)ORa, azidoalkyl, haloalkyl, nitroalkyl, cyanoalkyl, -alkylORa, -alkylOC(=O)Ra, -alkylSRa, -alkylSORa, -alkylSO2Ra,-alkylSO2NRa, -alkylSO2ORa, -alkylNRaRb, -C(H)=N(ORa), -C(alkyl)=N(ORa), -C(H)=NNRaRb, -C(alkyl)=NNRaRb, -C(H)(=NORa)NRaRb, -C(alkyl)(=NORa)NRaRb, -alkylN(Rb)NRaRb, -alkylN(Rb)C(=O)Ra,
Figure imgf000442_0001
-alkylN(Rb)SO2NRaRb, -alkylN(R )SO2Ra, -alkylC(=O)Ra, -alkylC(=O)ORa, -alkylC(=O)NRaRb and R13a; R13a is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R13a is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) and -alkylC(=O)N(alkyl)2;
Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle; wherein each Ra and Rb, at each occurrence, is independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, rήtroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, ■ -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Re;
alternatively, Ra and Rb, together with the nitrogen atom they are attached, form a heterocycle ring substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(afkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C(=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkylN(H)(alkyl), -alkylN(alkyl)2, -alkylN(H)C(=O)NH2, -alkylN(H)C(=O)N(H)(alkyl), -alkylN(H)C(=O)N(alkyl)2, -alkylC(=O)OH, -alkylC(=O)Oalkyl, -alkylC(=O)NH2, -alkylC(=O)N(H)(alkyl) -alkylC(=O)N(alkyl)2 and Re; and
Re is aryl, heteroaryl or heterocycle; wherein each Re is independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2, -SH, -S(alkyl), -SO2(alkyl), -N(H)C(=O)alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)NH2, -N(H)C(=O)N(H)(alkyl), -N(H)C(=O)N(alkyl)2, -C(=O)OH, -C=O)Oalkyl, -C(=O)NH2, -C(=O)N(H)(alkyl), -C(=O)N(alkyl)2, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH2, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)2, -alkyl-N(H)C(=O)NH2, -alkyl-N(H)C(=O)N(H)(alkyl), -alkyl-N(H)C(=O)N(alkyl)2, -alkyl-C(=O)OH, -alkyl-C(=O)Oalkyl, -alkyl-C(=O)NH2, -alkyl-C(=O)N(H)(alkyl) and -alkyl-C(=O)N(alkyl)2.
37. The compound of claim 36 wherein Ri is OH and R2 is H.
38. The compound of claim 36 wherein Ri is OH, R2 is H, X is O and R3 is alkyl, cycloalkenylalkyl, cycloalkylalkyl, heterocyclealkyl, heteroarylalkyl, arylalkyl, hydroxyalkyl, alkoxyalkyl, -alkylSRa, -alkylSORa, -alkylSO2Ra or -alkylNRaR .
39. The compound of claim 36 wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkyl and 1^ is aryl or heteroaryl.
40. The compound of claim 36 wherein Ri is OH, R2 is H, X is O, R3 is alkyl or cycloalkylalkyl and Rt is phenyl.
41. The compound of claim 36 wherein Ri is OH, R2 is H, X is O, R is alkyl or cycloalkylalkyl, t is phenyl substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halo, -OI ta, -NR4aR4b and
Figure imgf000444_0001
and R7 is alkyl; wherein ta and I tb are independently selected from the group consisting of hydrogen and alkyl.
42. The compound of claim 36 or a pharmaceutically acceptable salt form, stereoisomer, ester, salt of an ester, prodrag, salt of a prodrug, or combination thereof, selected from the group consisting of (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2-( {[methyl(2- pyridinylmethyl)amino]carbonyl}amino)pentanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-( { [[(2-isopropyl-l ,3- thiazol-4-yl)methyl](methyl)amino]carbonyl}amino)-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2-( {[methyl(2- pyridinylmethyl)amino]carbonyl}amino)butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-methyl-2-[( {methyl[(2- methyl- 1 ,3-thiazol-4-yl)methyl]amino} carbonyl)amino]butanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -2-( { [ {[2-(methoxymethyl)- l,3-thiazol-4-yl]methyl}(methyl)amino]carbonyl}amino)-3-methylbutanamide; (2S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-[({ethyl[(2-isopropyl-l,3- thiazol-4-yl)methyl]amino}carbonyl)amino]propanamide; (2S)-N-{(1S,2R)- 1 -benzyl-3-[(cyclopentyhnethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-({[[(2-isopropyl-l,3- thiazol-4-yl)methyl](methyl)amino]carbonyl}amino)-3-methylbutanamide; (25)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-({[[(2-isopropyl-l,3- thiazol-4-yl)methyl](methyl)amino]carbonyl}amino)-3-methylbutanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-({[methyl(2- pyridinylmethyl)amino]carbonyl}amino)pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-({[methyl(2- pyridinylmethyl)amino]carbonyl}amino)pentanamide; (2S,3R)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-tert-butoxy-2-({[{[2- (methoxymethyl)- 1 ,3 -thiazol-4-yl]methyl} (methyl)amino]carbonyl} amino)butanamide; (2S,3R)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -3-tert-butoxy-2-( {[ {[2- (methoxymethyl)-l,3-thiazol-4-yl]methyl}(methyl)amino]carbonyl}amino)butanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-3-[(cyclobutylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -2-( { [ { [2- (methoxymethyl)-l,3-thiazol-4-yl]methyl}(methyl)amino]carbonyl}amino)-3- methylpentanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-3-[(cyclopentylmethyl)( {4-[(E)~ (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -2-( { [ { [2- (methoxymethyl)-l ,3-thiazol-4-yl]methyl} (methyl)amino]carbonyl} amino)-3- methylpentanamide; (2S)-N {(1S,2R)- 1 -benzyl-3-[(cyclobutylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -3 -methyl-2- [( {methyl[(2- methyl- 1 ,3-thiazol-4-yl)methyl]amino} carbonyl)amino]butanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3 -methyl-2-[( {methyl[(2- methyl-l,3-thiazol-4-yl)methyl]amino}carbonyl)amino]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -3 -methyl-2- [( {methyl[(2- methyl-l,3-thiazol-4-yl)methyl]amino}carbonyl)amino]pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-tert-butoxy-2- [( {methyl[(2-methyl- 1 ,3-thiazol-4-yl)methyl] amino} carbonyl)amino]butanamide; (2S,3S)-N- {(1S,2R)- 1 -benzyl-3-[(cyclobutylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-tert-butoxy-2- [({methyl[(2-methyl-l,3-thiazol-4-yl)methyl]amino}carbonyl)amino]butanamide; (2S,35)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-({[methyl(3- nitrobenzyl)amino]carbonyl}amino)pentanamide; methyl 4-{(5S,8S,9R)-8-benzyl-9-hydroxy-l l-({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)-2,13-dimetlιyl-5-[(lS)-l-methylpropyl]-3,6-dioxo- 2,4,7, 11 -tetraazatetradec- 1 -yl} - 1 ,3-thiazol-2-ylcarbamate; (2S)-N- {(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2 -hydroxypropyl} -2-( { [ { [2- (methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} (methyl)amino]carbonyl} amino)-3- methylbutanamide; (2S,3S)-2-({[{[2-(acetylamino)-l,3-thiazol-4- yl]methyl} (methyl)amino] carbonyl} amino)-N- { ( 1 S,2R)- 1 -benzyl-3 - [(cyclobutyhnethyl)( {4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3- methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methyl-2-({[methyl(3- pyridinylmethyl)amino]carbonyl}amino)pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-methyl-2-({[methyl(4- pyridinylmethyl)amino]carbonyl}amino)pentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-({[{[2-(methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} (methyl)amino] carbonyl} amino)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-({[{[6- (methoxymethyl)-2-pyridinyl]methyl}(methyl)amino]carbonyl}amino)-3- methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-2-({[[(2-isopropyl-l,3- thiazol-4-yl)methyl](methyl)amino]carbonyl}amino)-3-methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-({[[(2-isopropyl-l,3- thiazol-4-yl)methyl](methyl)amino]carbonyl}amino)-3-methylpentanamide; (2S,3S)-2-( { [( {6- [(Z)-amino(hydroxyimino)methyl]-2- pyridinyl}methyl)(methyl)amino]carbonyl}amino)-N-{(lS,2R)-l-benzyl-3- [(cyclopentylmethyl)({4-[(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2- hydroxypropyl}-3-methylpentanamide; (2S)-N- {(1S,2R)- 1 -benzyl-3-[(cyclopentylmethyl)( {4-[(E (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -2-( { [ { [6- (methoxymethyl)-2-pyridinyl]methyl}(methyl)amino]carbonyl}amino)-3,3- dimethylbutanamide; (2»S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-({[{[6-(tert- butoxymethyl)-2-pyridinyl]methyl}(methyl)amino]carbonyl}amino)-3,3- dimethylbutanamide; (2S,3R)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-hydroxy-2-({[{[2- (methoxymethyl)-l,3-thiazol-4-yl]methyl}(methyl)amino]carbonyl}amino)butanamide; (2S,3R)-N- {(1S,2R)- 1 -benzyl-3-[(cyclopentylmethyl)( {4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)amino]-2-hydroxypropyl} -3-hydroxy-2-( {[ { [2- (methoxymethyl)- 1 ,3-thiazol-4-yl]methyl} (methyl)amino]carbonyl} amino)butanamide; (2S,3S)-2-({[(3-aminobenzyl)(methyl)amino]carbonyl}amino)-N-{(lS,2R)-l-benzyl- 2-hydroxy-3-[( {4-[(E)-(hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3- methylpentanamide; (2S,3R)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl} sulfonyl)(isobutyl)amino]propyl} -3-hydroxy-2-[( {methyl[(2- methyl- 1 ,3 -thiazol-4-yl)methyl] amino } carbonyl) amino]butanamide; (2S,3R)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3-hydroxy-2- [( {methyl[(2-methyl- 1 ,3 -thiazol-4-yl)methyl] amino} carbonyl)amino]butanamide; (2S,3S)-2-({[{[2-(aminomethyl)-l,3-thiazol-4- yl]methyl}(methyl)amino]carbonyl}amino)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)(isobutyl)amino]propyl}-3-methylpentanamide; (2S,35)-2-({[{[2-(aminomethyl)-l,3-thiazol-4- yl]methyl}(methyl)amino]carbonyl}amino)-N-{(lS,2R)-l-benzyl-3-[(cyclobutylmethyl)({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3- methylpentanamide; (2S,3S)-2-({[{[2-(aminomethyl)-l,3-thiazol-4- yl]methyl} (methyl)amino]carbonyl} amino)-N- {(1S,2R)- 1 -benzyl-3-[(cyclopentylmethyl)( {4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3- methylpentanamide; (2S,3S)-2-( { [( {2-[(lS)~ 1 -aminoethyl]-l ,3-thiazol-4- yl}methyl)(methyl)amino]carbonyl}amino)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3- methylpentanamide; (2S,3S)-2-({[({2-[(lR)-l-aminoethyl]-l,3-thiazol-4- yl}methyl)(methyl)amino]carbonyl}ainino)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3- methylpentanamide; (2S,3S)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4-[(E)- (hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-2-({[({6-[N- hydroxyethanimidoyl]-2-pyridinyl}methyl)(methyl)amino]carbonyl}amino)-3- methylpentanamide; and (2S,3S)-2-({[({2-[(lS)-l-(acetylamino)ethyl]-l,3-thiazol-4- yl}methyl)(methyl)amino]carbonyl}amino)-N-{(lS,2R)-l-benzyl-3-[(cyclopentylmethyl)({4- [(E)-(hydroxyimino)methyl]phenyl}sulfonyl)amino]-2-hydroxypropyl}-3- methylpentanamide.
43. A pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of claim 1, and a pharmaceutically acceptable carrier.
44. A pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of claim 1, one, two, three, four, five or six agents selected from the group consisting of a second HIN protease inhibitor, a HIN reverse transcriptase inhibitor, an HIN entry/fusion inhibitor, an HIN integrase inhibitor and an HIN budding/maturation inhibitor, or combination thereof, and a pharmaceutically acceptable carrier.
45. The pharmaceutical composition of claim 44 wherein the second HIN protease inhibitor is selected from the group consisting of ritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KΝI-272, DPC-681, DPC-684 and GW640385X.
46. The pharmaceutical composition of claim 44 wherein the HIN reverse transcriptase inhibitor is selected from the group consisting of lamivudine, stavudine, zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIN-210, Racivir (±-FTC), D-D4FC (Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz, capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC- 083), DPC-961, MIV-150, TMC-120 and TMC-125.
47. The pharmaceutical composition of claim 44 wherein the HIN entry/fusion inhibitor is selected from the group consisting of enfiivirtide (T-20), T-1249, PRO 2000, PRO 542, PRO 140, AMD-3100, BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D (SCH- D), TΝX-355 and UK-427857.
48. The pharmaceutical composition of claim 44 wherein the HIN integrase inhibitor is selected from the group consisting of S-1360, zintevir (AR-177), L-870812 and L-870810.
49. The pharmaceutical composition of claim 44 wherein the HIN budding/maturation inhibitor is PA-457.
50. A method of inhibiting the replication of an HIN viras comprising contacting said virus with a therapeuctially effective amount of a compound or combination of compounds of claim 1.
51. A method of treating or preventing an HIN infection comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of claim 1.
52. A method of treating or preventing an HIN infection comprising administering to a patient in need of such treatment a pharmaceutical composition of any one of claims 43, 44, 45, 46, 47, 48 and 49.
53. A method of inhibiting an HIN protease comprising contacting said HIN protease with a therapeutically effective amount of a compound or combination of compounds of claim 1.
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